Category Archives: Stem Cell Research

INTRODUCTION

Embryonic development is characterized by the temporal and spatial regulation of cell proliferation, migration, differentiation, and tissue formation. Although these processes are genetically determined, several signaling mechanisms including Wnt have been recognized as essential in regulating cell lineage specification and organogenesis (13).

The Na/Kadenosine triphosphatase (ATPase) (NKA), discovered in crab nerve fibers by Skou (4), belongs to the P-type ATPase superfamily. It has an enzymatic function that couples adenosine 5-triphosphate (ATP) hydrolysis to the transmembrane movement of Na+ and K+ in a cell lineagedependent manner. For example, while the NKA is involved in the formation of action potentials in excitable cells, its polarized distribution is key to the functionality of the epithelium.

In addition to its canonical enzymatic function, we and others have shown that the NKA has an enzymatic activityindependent signaling function through its interactions with membrane cholesterol and proteins such as Src, epidermal growth factor (EGF) receptor, and caveolin-1 (58). We use the term signaling with liberty here, referring to the ability of NKA to work as a receptor, a scaffold, and a signal integrator by regulating the functions of its interacting proteins. This newly appreciated signaling function of the NKA has been implicated in several cellular processes (912). However, direct genetic evidence supporting a role for NKA signaling in animal physiology and disease progression is still lacking. This is due, in part, to the technical difficulties in studying its signaling separately from its ATPase-mediated pumping function because the latter is required for the survival of animal cells (13). Fundamentally, it is unknown whether the signaling function is an intrinsic property of the protein NKA, as its Na+- and K+-driven enzymatic activity has been recognized as. Therefore, we were prompted to address two important questions: (i) Were the signaling and Na+/K+ transport functions of the NKA coevolved? (ii) If so, does the signaling function of NKA represent a primordial yet common mechanism for the regulation of a fundamental process in animal biology?

Structurally, the NKA is composed of both and subunits. The subunit contains the binding sites for Na+/K+ as well as ouabain, which are distinct from that of other P-type ATPases (14). It also has an N-terminal caveolin binding motif (CBM) proximal to the first transmembrane helix (fig. S1A). To assess the functionality of this motif, we made F97A and F100A mutations that map to the rat 1 NKA sequence. This strategy has been used by others to study the function of CBM in proteins other than the NKA (15). We used a knockdown and rescue protocol to generate a stable cell line (LW-mCBM) that essentially expresses just the CBM mutant 1, which was confirmed using [3H]ouabain binding assays (fig. S1B). Western blot and confocal imaging analyses showed that the expression of mutant 1 NKA in LW-mCBM was comparable to that in the control cell line, named AAC-19 cells (fig. S1, B and C). The expression of CBM mutant 1 was sufficient to restore the expression of the 1 subunit of the NKA, allowing normal plasma membrane targeting of the CBM mutant NKA in LW-mCBM cells (fig. S1, C and D). The successful generation of a stable CBM mutant 1 cell line suggests that the CBM is not essential for the enzymatic activity of the NKA because the ion-transporting function is necessary for animal cell survival (13). In further support, we conducted kinetic studies of the CBM mutant NKA. As shown in Fig. 1A, the overall enzymatic activity per unit of 1 NKA expression was identical between the control AAC-19 and LW-mCBM cells. The Km values of Na+, K+, and ouabain were comparable between the CBM mutant NKA and control (Fig. 1, B to D) (16). Together, these data indicate that the N-terminal CBM is not directly involved in the regulation of the enzymatic properties of the NKA.

(A) Crude membrane preparations were made from AAC-19 and LW-mCBM cells and measured for ouabain-sensitive ATPase activity as described in Material and Methods. (B) Ouabain concentration curve. Crude membrane from LW-mCBM cells was prepared and measured for ATPase activity in the presence of different concentrations of ouabain. Data are shown as percentage of control, and each point represents three independent experiments. Curve fit analysis and IC50 (median inhibitory concentration) were calculated by GraphPad. (C and D) Measurements of Na+ and K+ Km. Assays were done as in (B). The combined data were collected from at least three repeats, and Km value (means SEM) was calculated using GraphPad.

On the basis of the above, we next turned our attention to determining the effects of the CBM mutation on signaling capabilities of the 1 NKA. Specifically, we first conducted immunoprecipitation experiments. As we reported previously in many types of cells (8), immunoprecipitation of caveolin-1 coprecipitated 1 in AAC-19 cells. In contrast, mutation of the CBM resulted in an over 80% decrease in coprecipitated 1 in LW-mCBM cells (Fig. 2A).

(A) Cell lysates from AAC-19 and LW-mCBM were immunoprecipitated (IP) with polyclonal anticaveolin-1 antibody. Immunoprecipitated complex was analyzed by Western blot for 1 and caveolin-1 (n = 4). **P < 0.01 compared to AAC-19. (B) Cell lysates from AAC-19 and LW-mCBM cells were subjected to sucrose gradient fractionation as described in Materials and Methods. A representative Western blot of three independent experiments was shown. **P < 0.01 in comparison to AAC-19. (C) AAC-19 and LW-mCBM cells were treated with different concentrations of ouabain for 10 min and analyzed by Western blot. A representative Western blot was shown (n = 4). *P < 0.05 versus 0 mM ouabain. (D) Cell growth curves of AAC-19 and LW-mCBM. *P < 0.05 versus AAC-19 cells. (E) BrdU assay of AAC-19 and LW-mCBM. The values are means SEM from at least three independent experiments. Photo credit: Xiaoliang Wang, Marshall Institute for Interdisciplinary Research at Marshall University.

To substantiate these observations, we next conducted a detergent-free and carbonate-based density gradient fractionation procedure and found that 1 NKA and its main signaling partners (Src and caveolin-1) were co-enriched in the low-density caveolar fractions, as previously reported in epithelial cells (8, 17). In sharp contrast, the expression of the CBM mutant 1 caused the redistribution of these proteins from low-density to high-density fractions (Fig. 2B). Quantitatively, when the ratios of fraction 4/5 of each protein versus total were calculated, we found that the low-density fraction 4/5 prepared from the control AAC-19 cells contained ~60, ~70, and 80% of caveolin-1, Src, and 1 NKA, respectively. However, in LW-mCBM cells, only ~20% of caveolin-1, Src, and 1 NKA were detected in fraction 4/5 (Fig. 2B).

To address the functional consequences of the dissociation of the 1 NKA from its signaling partners in LW-mCBM cells, we exposed these cells to ouabain, a specific agonist of the receptor NKA/Src complex. As shown in Fig. 2C, while ouabain stimulated phosphorylation of extracellular signalregulated kinase (ERK), a downstream effector of the NKA/Src signaling pathway in AAC-19 cells (5, 8), it failed to do so in LW-mCBM cells.

We have previously shown that 1 NKA signaling is key to the dynamic regulation of cell growth (16, 18). As shown in Fig. 2D, LW-mCBM cells grew much slower than AAC-19 cells. 5-Bromo-2-deoxyuridine (BrdU) incorporation assays further verified that the expression of CBM mutant 1 resulted in an inhibition of cellular proliferation (Fig. 2E). In short, the above in vitro experiments indicate that the gain of CBM enables the NKA to perform the enzymatic activityindependent signaling functions.

With the preceding in vitro data suggesting that the CBM is critically important to the signaling function of the NKA, we next set forth to test the physiological significance of this finding. Thus, we generated a knock-in mouse line expressing the aforementioned CBM mutant 1. The CBM mutant (mCBM) mouse was generated using the Cre/LoxP gene targeting strategy (19), as depicted in fig. S2A. The chimeric offspring were crossed to C57BL6 females to yield mCBM heterozygous mice, and the desired F97A and F100A substitutions were verified (fig. S2B). mCBM heterozygous mice were born fertile and survived to adulthood. Our attempts to generate mCBM homozygous mice yielded no viable homozygous pups (Fig. 3A) in nearly 400 young mice genotyped by polymerase chain reaction (PCR). These results document for the first time that the CBM in the 1 subunit of the NKA represents a fundamental signaling mechanism essential for mouse embryonic development and survival.

(A) Early embryonic lethality of mCBM homozygous embryos. (B) Morphological comparison and body size of wild-type (WT) (top), heterozygous (middle), and homozygous (bottom) mCBM embryos at E9.5. Black bars, 0.3 mm. The arrows show the abnormal head morphology. Body size was measured from at least 12 embryos in different genotypes by ImageJ. Data are presented as means SEM. ***P < 0.01 versus the average of WT. (C) Sagittal sections of WT and homozygous (Homo) and heterozygous (Het) embryos at E9.5 with hematoxylin and eosin (H&E) staining. Homozygous embryos that had defective brain development indicated by open arrows. (D) Brain cross section of WT, homozygous, and heterozygous embryos at E9.5 with H&E staining. Homozygous embryos that had unclosed neural tube in forebrain, midbrain, and hindbrain were indicated by arrows; WT and heterozygous E9.5 embryos with closed neural tube were indicated by arrowhead. (E) Morphological comparison of WT and Na/K-ATPase 1 (+/) embryos at E9.5. White bars, 0.3 mm (n = 5 to 7). Photo credit: Xiaoliang Wang, Marshall Institute for Interdisciplinary Research at Marshall University.

There is evidence that endogenous ouabain is important in animal physiology because of its role in stimulating the signaling function of the NKA (10, 19, 20). Because the loss of the CBM abolishes ouabain-induced signal transduction in vitro, we tested whether administration of pNaKtide, a specific inhibitor of the receptor NKA/Src complex (21), would cause the same embryonic lethality as we observed in mCBM mice. As depicted in fig. S3, we observed no change in fetal survival after administration of pNaKtide to female mice before mating and continued until the end of pregnancy. It is important to mention that pNaKtide has been proven to be specific and effective in blocking the NKA/Src receptor signaling in vivo (2226), and our control experiments showed that pNaKtide could cross the placental barrier. Moreover, this lack of pNaKtide effect on mouse embryogenesis appears to be consistent with a previous report demonstrating that neutralization of endogenous ouabain by injection of an anti-ouabain antibody did affect the kidney development of neonatal mice but did not affect their overall survival (20). On the basis of these, we concluded that the NKA/Src receptor function in the CBM mutant embryo was not the direct cause of lethality and set out to identify a hitherto unrecognized NKA CBM-dependent yet NKA-Srcindependent underlying mechanism.

Embryo implantation within mice occurs around embryonic day 4.5 (E4.5) (27), followed by gastrulation around E5.5 to E7.5 (28), when the simple embryo develops into an organized and patterned structure with three germ layers (29). Subsequently, organogenesis takes place at E8.0 and onward; the patterned embryo starts to develop its organ systems including the brain, heart, limbs, and spinal cord.

To further analyze and explore the molecular mechanisms of the CBM mutation in the embryonic development of mice, we harvested the fertilized eggs at E1.5, and cultured them in vitro. It has previously been demonstrated that 1 knockout results in the failure of blastocyst formation (13). In contrast, we found that eggs from mCBM heterozygous parents developed into morphologically normal blastocysts. These findings indicate that loss of the CBM does not affect the molecular mechanisms necessary for blastocyst formation. Thus, a loss of functional 1 CBM and complete knockout of 1 NKA both result in embryonic lethality but differ by their specific mechanisms. Knockout of 1 NKA inevitably causes the loss of NKA enzymatic function, which is incompatible with life (13), and results in the failure of blastocyst formation in mice. In contrast, our in vitro data indicate that a loss of the CBM does not cause any notable alteration in NKA enzymatic activity, which is supported by the observation that mCBM mice are still capable of producing morphologically normal blastocysts. Consequently, CBM role in development appears to be critical at a developmental stage beyond blastocyst stage, and we further set out to identify this stage.

To this end, we collected and genotyped embryos or yolk sacs from mCBM heterozygous mice at different days of gestation. We first dissected 31 embryos at E12.5 from three different mice (Fig. 3A). Reabsorption and empty deciduae were observed in six implantation sites with only the mothers genotype detectable. At E9.5, we were able to dissect a total of 303 embryos. Sixty-four of them were mCBM homozygous (21%), 71 were wild-type (23%), and 168 were mCBM heterozygous (55%) (Fig. 3A).

To further analyze the embryonic developmental defects, we examined mCBM embryos at E7.5, E8.5, and E9.5. The embryos looked similar between wild-type and mCBM homozygous mice at E7.5 and E8.5 under dissection microscopy. However, we found several severe morphological defects in homozygous embryos at E9.5 (Fig. 3, C and D). First, the overall size of embryos was considerably reduced in mCBM homozygous embryos (about 35% the size of the wild-type embryos). In addition, the observed effect of the CBM mutant on embryonic size was gene dose dependent, as the mCBM heterozygous embryos were significantly smaller than those of wild-type embryos but much bigger than the homozygous embryos. Second, most homozygous embryos did not turn, a process normally initiated at E8.5, suggesting that the loss of a functional CBM was responsible for a developmental arrest at an early stage of organogenesis. Last, the most severe morphological defects were observed in the heads of the mCBM homozygous embryos. In addition to the reduced size (about 25% of the size of wild-type embryos), we observed that mCBM homozygous embryos failed to close their cephalic neural folds (anterior neuropore) as indicated by the arrow in Fig. 3B. This phenotype more closely resembled wild-type embryos at E8.0 to E8.5, suggesting again that the loss of CBM arrested organogenesis in its early stages. On the other hand, all heterozygous embryos, although smaller than wild-type embryos, showed normal head morphology (Fig. 3B).

To follow up on the above observations, we collected and made histological sections of wild-type, heterozygous, and homozygous embryos at E9.5 (Fig. 3, C and D). Normally, formation and closure of the anterior neuropore occurs at E9.5 (Fig. 3D). In sharp contrast, mCBM homozygous embryos developed defects in neural closure. Specifically, failure of neural tube closure at the level of forebrain, midbrain, and hindbrain was prominent in homozygous embryos (Fig. 3D).

To further explore the molecular mechanism by which the loss of the CBM led to defects in organogenesis, we next conducted RNA sequencing analyses (RNAseq) in wild-type and mCBM homozygous embryos. More than 17,000 genes were read out in either mCBM homozygous or wild-type samples. Data analyses indicated that 214 and 208 genes from mCBM homozygous embryos were significantly down- and up-regulated, respectively (fig. S4). Among them, the expression of a cluster of transcriptional factors important for neurogenesis was significantly reduced. As depicted in Fig. 4A, the expression of neurogenin 1 and 2 (Ngn1/2), two basic helix-loop-helix (bHLH) transcriptional factors (30), was significantly down-regulated in homozygous embryos. Ngn1/2 are considered to be determination factors for neurogenesis, while members of the NeuroD family of bHLH work downstream to promote neuronal differentiation (31). We found that the expression of NeuroD1/4 was further reduced in mCBM homozygous embryos. As expected from these findings, the marker of neural stem cells nestin (Nes) and other genes related to neurogenesis including huntington-associated protein 1 (Hap1), nuclear receptor subfamily 2 group E members 1 (Nr2e1), and adhesion G protein (heterotrimeric guanine nucleotidebinding protein)coupled receptor (Adgrb1) were all down-regulated in mCBM homozygous embryos (Fig. 4A). To verify these data, we performed reverse transcription quantitative PCR (RT-qPCR) analyses of both wild-type and mCBM homozygous embryos collected at E9.5. As depicted in Fig. 4 (B to D), the aforementioned transcriptional factors were all down-regulated in a cascade fashion. While a modest reduction was found with Ngn1/2, the expression of NeuroD1/4 was almost completely inhibited. To test whether the effects of the CBM mutation on the expression levels of these transcriptional factors were gene dose dependent, we also examined mRNA levels of Ngn1/2 and NeuroD1/4 in mCBM heterozygous embryos. As depicted in Fig. 4 (B and C), the expression of these genes followed the pattern found in homozygous embryos. The expression level in heterozygous embryos was significantly reduced compared to wild-type embryos but was much higher than that of mCBM homozygous embryos. These gene dosingdependent cascade effects suggest that the 1 NKA is an important upstream regulator but not a determinant of neurogenesis like Ngn1/2 (32) or a key receptor mechanism like Wnt is.

(A) RNAseq results of several neurogenesis and neural stem cell markers. Log2 ratio = 1 means twofold of change. *P < 0.05 compared to WT. (B and C) RT-qPCR analysis of selected gene expression in WT, heterozygous, and homozygous mCBM embryos at E9.5. (D) RT-qPCR analysis of neural stem cell marker gene expression in WT and homozygous mCBM E9.5 embryos. (E) RT-qPCR analysis of neurogenesis marker genes in WT and NKA 1+/ mouse E9.5 embryos. Quantitative data are presented as means SEM from at least six independent experiments. *P < 0.05, **P < 0.01 versus WT control.

As a control, we also assessed the expression of different isoforms of NKA and caveolin-1. As depicted in fig. S5, no changes were detected in the expression of the 1 isoform of the NKA. This is expected, as the mutations were only expressed on exon 4. Previous reports have demonstrated that, in addition to the 1 isoform, neurons also express the 3 isoform, while muscle and glial cells express the 2 isoform of the NKA (9). No difference was observed in the expression of 3, while the expression of 2 was too low to be measured. We were also unable to detect any change in the expression of caveolin-1.

The total amount of protein recognized by the anti-NKA 1 antibody is unchanged in mCBM heterozygous mouse tissues compared to that of the wild type, albeit with changes in distribution in caveolar versus noncaveolar fractions. This indicates that the CBM mutant protein is fully expressed, as observed in cells (fig. S1), and further demonstrates that a reduction of enzymatic activity is not responsible for the observed phenotype in mCBM homozygous embryos. However, because the expression of wild-type 1 in mCBM heterozygous animals is most likely reduced, the phenotypic changes we observed in these mice could be due to the reduction of wild-type 1 expression rather than the expression of CBM mutant 1. To address this important issue, we collected embryos from 1 NKA heterozygous (1+/) mice and their littermate controls (33). In contrast to mCBM heterozygotes, reduction of 1 expression alone did not change the size of embryos (Fig. 3D), head morphology, or the expression of neuronal transcriptional factors (Fig. 4E). Because NKA 1 haploinsufficiency did not phenocopy mCBM heterozygosity, it was concluded that the mCBM allele was responsible for the observed changes.

The CBM in NKA has a consensus sequence of FCxxxFGGF (fig. S6). To assess the generality of CBM-mediated regulation, we first turned to the conserveness of the CBM in animal NKA. A database search reveals that, like Wnt, the mature form of NKA (i.e., containing CBM, Na+/K+ binding sites, and subunit) is absent in unicellular organisms but present in all multicellular organisms within animal kingdom (fig. S6). Further analysis of published data confirms the coevolutionary nature of the CBM and the binding sites for Na+ and K+ in the NKA. The first indication is from the analysis of single-cell organisms. No mature form of NKA is found in these organisms (fig. S6A). However, Salpingoeca rosetta, a marine eukaryote belonging to the Choanoflagellates class, undergoes a very primitive level of cell differentiation and specialization in their life cycle and expresses a putative NKA with several conserved motifs involved in the binding of Na+/K+. On the other hand, it contains no CBM (fig. S6) and there is also no evidence that it expresses a subunit.

Second, as depicted in figs. S6 and S7, Caenorhabditis elegans, an example of a metazoan organism, expresses a mature form of NKA (eat-6) that contains binding sites for Na+ and K+ as well as the N-terminal CBM. It also expresses a couple of putative NKA such as catp-2 (34). However, they contain neither the CBM nor Na+ and K+ binding sites.

Third, although the X amino acids in the NKA CBM in invertebrates vary, only conserved substitutions occurred in this motif. This is in sharp contrast to many other membrane receptors/transducers such as Patched and G that also contain a consensus CBM (figs. S6 and S7). Within vertebrates, the CBM sequence FCRQLFGGF in NKA remains completely conserved across all species. Moreover, this sequence remains conserved in all isoforms of the subunit except for the 4 isoform, which is exclusively expressed in sperm. The 4 isoform in some species still adapts the CBM sequence found in invertebrates (fig. S6). Moreover, of a total of nine subunits found in zebrafish (35), five appear to be 1 homologs that, like the 4 isoform, contain both vertebrate and invertebrate CBM sequences.

Last, turning to the evolutionary aspect of the receptor NKA/Src complex, we found that the Src-binding NaKtide and Y260 sequences, in sharp contrast to the CBM, are only conserved in mammalian ATP1A1 (fig. S7). Therefore, the NKA/Src receptor may have evolved after the acquisition of the CBM, and hence is not a part of the fundamental regulation of animal organogenesis (fig. S3).

In short, the N-terminal CBM, like the binding sites for Na+ and K+, is conserved in all subunits of NKA in animals, even after taking into consideration gene duplications and the generation of different isoforms or homologs. Thus, we postulate that this CBM must be evolutionally conserved to enable the NKA, in parallel with its enzymatic function, to serve an important role in the origination of multicellular organisms within the animal kingdom.

Organogenesis represents a unique feature of multicellular organisms. In considering the preceding findings, we reasoned that the loss of NKA CBM would also affect embryonic development in invertebrates such as C. elegans. To test our hypothesis, we used CRISPR-Cas9 to knock in the equivalent CBM double mutations of F75A and F78A in C. elegans NKA gene eat-6 (named as syb575) (fig. S8). Similar to the impact of the expression of CBM mutant 1 NKA in mice, no homozygous worms were produced, whereas the heterozygous worms hatched normally. Moreover, by using the gene balancer nT1, we confirmed that the F75A and F78A double mutations induced embryonic lethality in syb575 homozygotes secondary to L1 arrest (Fig. 5A). Furthermore, the observed larval arrest due to the loss of the eat-6 CBM was rescued by a transgene expressing a wild-type eat-6 complementary DNA (cDNA) through an extrachromosomal array (Fig. 5B). The lethality phenotype in syb575 mutants was different from those of the eat-6 mutants defective in enzymatic (transport) activity, because while the eat-6 mutants had growth defects, they were able to grow past the L1 stage (36). An exception to this was a cold-sensitive eat-6 (ad792) mutant with severely reduced transport activity, which exhibited L1 arrest at lower temperatures similarly to the syb575 mutant worms (36). Overall, those data suggest that both CBM-mediated signaling and ion transport activity by the NKA are essential to full-scale organogenesis in C. elegans.

(A) Heterozygous CBM mutant (mCBM) worms syb575/nT1 have GFP signals in pharynx (pointed with the arrowhead), while mCBM homozygous worms are GFP negative and arrested at larval stage (pointed with an arrow). (B) Rescue with a WT eat-6 gene showing a mCBM homozygous worm with a transgenic marker sur-5::GFP. Arrow points the somatic GFP signals. (C) Mutation of CBM1 NKA (F97A; F100A) results in reduced colony formation in human iPSC (mCBM iPSC). (D) RT-qPCR analysis of stem cell markers and primary germ layer markers in WT and mCBM iPSC. *P < 0.05 compared to WT. n = 7. Photo credit: Liquan Cai, Marshall Institute for Interdisciplinary Research at Marshall University.

In short, our data indicate that loss of the NKA CBM results in defective organogenesis in both mice and C. elegans. This, together with our finding that the NKA CBM is conserved in all NKA regardless of isoform or homolog, indicates that the NKA was originally evolved as a dual functional protein in multicellular organisms, and that it represents a primordial and common mechanism for regulating stem cell differentiation and early stage of organogenesis in animals.

Turning now to even more general features of the CBM in organogenesis, we searched for the plant plasma membrane H-ATPase that functions equivalently to the animal NKA. Like the NKA, the plant plasma membrane H-ATPase also contains a sequence motif at the first transmembrane segment that is in accordance with the consensus CBM. This motif is completely conserved from blue algae to land plants but does not exist within yeast and bacteria (fig. S6).

To assess the human relevance of our findings, we used CRISPR-Cas9 gene editing to generate the same mutations in human induced pluripotent stem cells (iPSCs) (fig. S9). As depicted in Fig. 5C, the expression of mutant CBM 1 reduced the colony formation ability of human iPSCs. Concomitantly, this was accompanied by a significant reduction in the expression of stemness markers (both Nanog and Oct4), and transcriptional factors controlling germ layer differentiation (gene MIXL and T for mesoderm, OTX2 and SOX1 for ectoderm, and GATA4 and SOX17 for endoderm) (Fig. 5D). These findings confirm an essential role of the NKA CBM in the regulation of stem cell differentiation and suggest the potential utility of targeting the NKA for improving tissue regeneration.

The canonical Wnt pathway is made of multiple components localized in the plasma membrane and cytosol (2, 3). Functionally, this pathway is critically important in animal organogenesis (2, 37). For example, it plays an essential role in the establishment of neurogenic niches and regulates the differentiation of neural stem cells into neuroblasts during organogenesis by regulating the expression of transcriptional factors Ngn and NeuroD (37, 38). Thus, we were prompted by the observed neural defects in mice to test whether the expression of the CBM mutant 1 NKA affects Wnt/-catenin signaling.

In the first set of studies, we examined the cellular distribution of -catenin in LW-mCBM cells. As depicted in Fig. 6A, confocal imaging analysis showed that -catenin was distributed away from the plasma membrane in a vesicle-like form in LW-mCBM cells. To verify this finding, we fractionated the cell lysates as performed in Fig. 3B and observed that -catenin, like Src and caveolin-1, moved from the low-density fractions to high-density fractions when compared to control cells (Fig. 6B). Control experiments showed no changes in the expression of E-cadherin, glycogen synthase kinase3 (GSK-3), LRP5/6 (Low-density lipoprotein receptor-related protein 5 and 6), and -catenin in LW-mCBM cells (Fig. 6C).

(A) -Catenin staining of AAC-19 and LW-mCBM at basal level (n = 5). Blue arrow indicated -catenin signal in the cytoplasm of cells. (B) Sucrose gradient fractionation of -catenin in AAC-19 and LW-mCBM cells (n = 3). **P < 0.01. (C) Western blot analysis of Wnt/-catenin signaling proteins in AAC-19, LX-2, and LW-mCBM cells from at least six independent experiments. Two samples from each cell lines are presented. (D) Wnt3a induced TOPFlash luciferase report assay in AAC-19 and LW-mCBM (n = 8). ***P < 0.01. (E) Wnt3a induced expression of Wnt/-catenin targeting genes (n = 8). **P < 0.01. (F) Wnt3a induced TOPFlash luciferase report assay in AAC-19, LX-2, and LW-mCBM cells (n = 4). ***P < 0.01.

To test whether these changes in -catenin distribution alter the function of canonical Wnt signaling, we conducted a TOPFlash luciferase activity assay (39). Cells were transiently transfected with the reporter plasmid, exposed to Wnt3a conditional medium, and then subjected to TOPFlash luciferase assays. As shown in Fig. 6D, while Wnt3a induced a greater than 35-fold increase in luciferase activity in AAC-19 cells, it only produced a fourfold increase in LW-mCBM cells, which equates to an approximate 90% reduction in the dynamics of Wnt activation. To further test the impact of the CBM mutation on Wnt signaling, we examined the effects of Wnt3a on the expression of Wnt target genes. Cells were exposed to Wnt3a for 6 hours and subjected to RT-qPCR analysis. As depicted in Fig. 6E, while Wnt3a increased the expression of c-Myc, Lef, and NKD1 expression in AAC-19 cells, it failed to do so in LW-mCBM cells.

On the basis of the above observations, we reasoned that the NKA CBM might play an essential role in the dynamic regulation of Wnt signaling. We therefore analyzed Wnt signaling in our LX-2 cell line. This cell line was made by the same strategy used for the generation of LW-mCBM cells, and it expresses essentially just the 2 isoform (40). We have observed that 2 NKA, like CBM mutant 1, maintains cellular pumping capacity but is unable to signal via Src like a wild-type 1 NKA (40). However, unlike CBM mutant 1, 2 does contain the same CBM at the N terminus (fig. S6). As depicted in Fig. 6F, expression of the 2 isoform produced a rescue of Wnt signaling dynamics when compared to that in LW-mCBM cells, which reinforces the idea that the NKA CBM is key to the dynamics of Wnt signaling. Like in LW-mCBM cells, no change in -catenin expression was noted in LX-2 cells. However, compared to LW-mCBM cells, caveolin-1 expression was decreased in LX-2 cells, while ERK activity was increased (Fig. 6C). Together, these findings suggest that the conserved NKA CBM is essential for regulating Wnt signaling, which is independent of the pumping or CTS (ardiotonic steroid)activated Src-dependent signaling transduction.

To see whether there is evidence of Wnt signaling defects in mCBM homozygous embryos, we examined the RNAseq data using a tool kit of pathway analysis. As depicted in fig. S10, Wnt signaling appears to be defective at the transcriptional level. First, the expression of one of the Wnt receptors [Frizzled homolog 5 (Fzd5)] and one of the Wnt ligands (Wnt7b) was down-regulated (fig. S10A). Second, the Wnt/-catenin signaling inhibitor, secreted frizzled-related protein 5 (Sfrp5), was up-regulated in mCBM homozygous embryos. Third, the -catenin destruction complex component adenomatosis polyposis coli (APC) was down-regulated in mCBM homozygous embryos. All these defects in Wnt signaling were confirmed by RT-qPCR analysis of both wild-type and mCBM homozygous embryos at E9.5 (fig. S10B). In addition, APC down-regulation was also observed at the protein level in mCBM iPSCs (fig. S10C). Last, the defect in Wnt signaling was further substantiated by the altered expression of Wnt downstream target genes. As shown in fig. S10B, the expression of Lef and NKD1 was significantly reduced in mCBM homozygous embryos. The expression of c-Myc was too low to be detected.

Together, these data provide strong support to the notion that the CBM is a key to the regulation of Wnt by the NKA. We hypothesize that this critical function of the NKA CBM may explain why the CBM is conserved in all four subunit isoforms of the NKA. It is important to mention that the specific molecular defects in Wnt signaling that we have identified were tested in epithelial cells, a model we have previously used to characterize 1-specific signaling functions (16, 41). In view of the cell/tissue specificity of both NKA expression and subunit assemble (42) and Wnt signaling (13, 37), it is likely that this mechanism does not fully explain the Wnt signalingrelated defects in embryogenesis.

The enzymatic function of NKA coordinates the transmembrane movement of Na+/K+, which is essential for the survival of individual animal cells. At the tissue/organ level, the ATP-powered transport of Na+/K+ by the NKA is required for neuronal firing, muscle contraction, and the formation and functionality of epithelia and endothelia. The NKA was found to be essential for forming septate junction in Drosophila melanogaster (43, 44) via a regulatory mechanism independent of its ion-pumping activity. Here, we reveal an additional fundamentally important role of NKA in the regulation of signal transduction through a separate functional domain (CBM) unrelated to its enzymatic activity.

Our findings raise the question of why NKA acquired the CBM in addition to its binding sites for Na+ and K+. One possible explanation for this is that the additional functionality in NKA (fulfilled by the CBM) evolved for the purpose of regulating stem cell differentiation and organogenesis in multicellular organisms. Two observations support this hypothesis. First, both Wnt and NKA are present in the first multicellular organisms within the animal kingdom and are evolutionally conserved ever since. Thus, it is likely that the NKA and Wnt work in concert to enable stem cell differentiation and organogenesis in animals. Second, while Wnt is key to the cellular programs of stemness and cell lineage specification (2), it does not directly participate in cell lineagespecific activities of newly differentiated cells. Instead, this particular function might be fulfilled by the NKA. Conceivably, the NKA could have been evolved, as exemplified by the mitochondrial cytochrome c in ATP generation, to bring together two seemingly unrelated processes (i.e., Wnt signaling regulation via the CBM and ion transport through Na+ and K+ binding) into one signaling circuitry, which is critical to the dynamic regulation of transcriptional factors that are required for organogenesis in a temporally and spatially organized manner. Needless to say, this hypothesis remains to be tested. In addition, other important signaling pathways such as Notch and Sonic Hedgehog may also be regulated by NKA.

It is also of interest to note the evolutionary conserveness of the CBM in the plant plasma membrane H-ATPase. Like its counterpart within the animal kingdom, the plasma membrane H-ATPase is essential for plant organogenesis (45). Unlike the NKA, the plasma membrane H-ATPase exists in single-celled organisms such as yeast, and their ion-pumping function is regulated by similar mechanisms (46). However, yeast, with no use for cellular machinery needed for organogenesis, does not contain the H-ATPase with conserved CBM. Moreover, we also observed that no CBM exists in the plasma membrane Ca-ATPase (fig. S6), both of which belong to the same type II P-type ATPase family as the NKA. While the Ca-ATPase is a more ancient protein than the NKA, as its expression can be found in unicellular organisms, the H/K-ATPase appeared later than the NKA, at some point during the development of vertebrates. Thus, we suggest that the NKA may have evolved from a P-ATPase of unicellular organisms via the gain of both the CBM and Na+/K+ binding sites. In contrast, the H/K-ATPase may have evolved from the NKA, losing not only the Na+ binding site but also the CBM.

We have shown a direct interaction between the NKA and caveolin-1 (8, 17), which has been independently confirmed (47). The loss of the CBM significantly reduced the interaction between NKA and caveolin-1 as revealed by multiple assays. In addition to caveolin-1, we and others have reported several signal transductionrelated interactions (48). Of these, the potential interaction between 1 NKA and Src has attracted the most attention, especially in the past 10 years (7). While most studies indicated an important role of Src in CTS-activated signal transduction via 1 NKA, several publications have questioned whether 1 NKA interacts with Src directly to regulate Src functionality (49, 50). While this important difference remains to be experimentally addressed, we would like to point out the following facts. First, while we recognize the merit of using purified protein preparation to study protein interaction, it is important to recognize the limitation of using purified Src from bacterial expression system because they are heterogeneously phosphorylated. Second, we have reported multiple lines of evidence that support a direct interaction between 1 NKA and Src, including the identification of isoform-specific Src interaction, the mapping of potential Src-interacting sites in the 1 isoform, and the development of pNaKtide as Src inhibitor and receptor antagonist. These findings have substantially increased our understanding of 1 NKA/Src interaction in cell biology and animal physiology. It is important to mention that several groups not associated with us have successfully used pNaKtide to block ouabain and NKA signaling in vitro and in vivo (2326, 51). While our group and others continue to characterize the molecular basis and biological function of the NKA/Src receptor complex, we propound that the question of NKA/caveolin-1 interaction is a more pressing one in the context of this study. The role of CBM in caveolin-protein interaction and caveolae-related signaling is still debated (41, 52, 53).

Last, we conclude from these interesting findings that the NKA is not just an ion pump or a CBM-directed regulator but a critical multifunctional protein. This whole functionality underlies a hitherto unrecognized common mechanism essential for stem cell differentiation and organogenesis in multicellular organisms within the animal kingdom. Moreover, many recent studies also support the concept that the 1 NKA has acquired more functional motifs (e.g., Src-binding sites for the formation of NKA/Src receptor complex) during evolution. In addition, we have demonstrated that either knockdown of 1 NKA or the expression of an N-terminal fragment containing the CBM of the 1 subunit was sufficient to attenuate purinergic calcium signaling in renal epithelial cells (54). The 1 NKA is also found to be essential for CD36 and CD40 signaling in macrophages and renal epithelial cells (55, 56). Aside from the profound biological and fundamental implications, the previously unidentified NKA-mediated regulation of Wnt signaling through its N-terminal CBM may have substantial implications in our understanding of disease progression. The rapidly increasing appreciation of Wnt signaling in the pathogenesis of cancer and cardiovascular diseases (2, 3, 38) underlies the potential utility of NKA as a multidrug target (12, 22, 57, 58).

Acknowledgments: Funding: This work was supported by grants from: National Institutes of Health (NIH) Research Enhancement Award (R15) (R15 HL 145666); American Heart Association (AHA) Scientist Development Grant (#17SDG33661117); Brickstreet Foundation and the Huntington Foundation, which provide discretionary funds to the Joan C. Edwards School of Medicine. (These funds are both in the form of endowments that are held by Marshall University). Author contributions: Conceptualization: Z.X., X.W., J.X.X., L.C., G.-Z.Z., S.V.P., and J.I.S.; methodology: X.W., L.C., I.L., D.W., and G.-Z.Z.; investigation: X.W., L.C., X.C., J.W., Y.C., and J.Z.; writing (original draft): X.W., J.X.X., and Z.X.; writing (review and editing): Z.X., J.X.X., L.C., J.I.S., S.V.P., D.W., G.-Z.Z., and X.W.; funding acquisition: Z.X.; visualization: X.W. and Z.X. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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A caveolin binding motif in Na/K-ATPase is required for stem cell differentiation and organogenesis in mammals and C. elegans - Science Advances

LOS ANGELES, United States:QY Research has recently published a report, titled Global Stem Cell Equipment Market Research Report 2020-2026.The research report provides an in-depth explanation of the various factors that are likely to drive the market. It discusses the future of the market by studying the historical details. Analysts have studied the ever-changing market dynamics to evaluate their impact on the overall market. In addition, the Stem Cell Equipment report also discusses the segments present in the market. Primary and secondary research methodologies have been used to provide the readers with an accurate and precise understanding of the overall Stem Cell Equipment market. Analysts have also given readers an unbiased opinion about the direction companies will take during the forecast period.

The research report also includes the global Stem Cell Equipment market figures that provide historical data as well as estimated figures. It gives a clear picture of the growth rate of the market during the forecast period. The Stem Cell Equipment report aims to give the readers quantifiable data that is collected from verified data. The report attempts to answer all the difficult questions such as market sizes and company strategies.

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The vendor landscape and competitive scenarios of the global Stem Cell Equipment market are broadly analyzed to help market players gain competitive advantage over their competitors. Readers are provided with detailed analysis of important competitive trends of the global Stem Cell Equipment market. Market players can use the analysis to prepare themselves for any future challenges well in advance. They will also be able to identify opportunities to attain a position of strength in the global Stem Cell Equipment market. Furthermore, the analysis will help them to effectively channelize their strategies, strengths, and resources to gain maximum advantage in the global Stem Cell Equipment market.

Key Players Mentioned in the Global Stem Cell Equipment Market Research Report: Chart, Worthington Industries, Cesca Therapeutics, Shengjie Cryogenic Equipment, Sichuan Mountain Vertical, Qingdao Beol

Global Stem Cell Equipment Market Segmentation by Product: Stem Cell Cryopreservation Equipment, Stem Cell Separation Equipment, Others

Global Stem Cell Equipment Market Segmentation by Application: Cord Blood Stem Cells Cryopreservation, Other Stem Cells Cryopreservation

The report comes out as an accurate and highly detailed resource for gaining significant insights into the growth of different product and application segments of the global Stem Cell Equipment market. Each segment covered in the report is exhaustively researched about on the basis of market share, growth potential, drivers, and other crucial factors. The segmental analysis provided in the report will help market players to know when and where to invest in the global Stem Cell Equipment market. Moreover, it will help them to identify key growth pockets of the global Stem Cell Equipment market.

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Table of Content

1 Study Coverage1.1 Stem Cell Equipment Product Introduction1.2 Key Market Segments in This Study1.3 Key Manufacturers Covered: Ranking of Global Top Stem Cell Equipment Manufacturers by Revenue in 20191.4 Market by Type1.4.1 Global Stem Cell Equipment Market Size Growth Rate by Type1.4.2 Stem Cell Cryopreservation Equipment1.4.3 Stem Cell Separation Equipment1.4.4 Others1.5 Market by Application1.5.1 Global Stem Cell Equipment Market Size Growth Rate by Application1.5.2 Cord Blood Stem Cells Cryopreservation1.5.3 Other Stem Cells Cryopreservation1.6 Coronavirus Disease 2019 (Covid-19): Stem Cell Equipment Industry Impact1.6.1 How the Covid-19 is Affecting the Stem Cell Equipment Industry1.6.1.1 Stem Cell Equipment Business Impact Assessment Covid-191.6.1.2 Supply Chain Challenges1.6.1.3 COVID-19s Impact On Crude Oil and Refined Products1.6.2 Market Trends and Stem Cell Equipment Potential Opportunities in the COVID-19 Landscape1.6.3 Measures / Proposal against Covid-191.6.3.1 Government Measures to Combat Covid-19 Impact1.6.3.2 Proposal for Stem Cell Equipment Players to Combat Covid-19 Impact1.7 Study Objectives1.8 Years Considered

2 Executive Summary2.1 Global Stem Cell Equipment Market Size Estimates and Forecasts2.1.1 Global Stem Cell Equipment Revenue Estimates and Forecasts 2015-20262.1.2 Global Stem Cell Equipment Production Capacity Estimates and Forecasts 2015-20262.1.3 Global Stem Cell Equipment Production Estimates and Forecasts 2015-20262.2 Global Stem Cell Equipment Market Size by Producing Regions: 2015 VS 2020 VS 20262.3 Analysis of Competitive Landscape2.3.1 Manufacturers Market Concentration Ratio (CR5 and HHI)2.3.2 Global Stem Cell Equipment Market Share by Company Type (Tier 1, Tier 2 and Tier 3)2.3.3 Global Stem Cell Equipment Manufacturers Geographical Distribution2.4 Key Trends for Stem Cell Equipment Markets & Products2.5 Primary Interviews with Key Stem Cell Equipment Players (Opinion Leaders)

3 Market Size by Manufacturers3.1 Global Top Stem Cell Equipment Manufacturers by Production Capacity3.1.1 Global Top Stem Cell Equipment Manufacturers by Production Capacity (2015-2020)3.1.2 Global Top Stem Cell Equipment Manufacturers by Production (2015-2020)3.1.3 Global Top Stem Cell Equipment Manufacturers Market Share by Production3.2 Global Top Stem Cell Equipment Manufacturers by Revenue3.2.1 Global Top Stem Cell Equipment Manufacturers by Revenue (2015-2020)3.2.2 Global Top Stem Cell Equipment Manufacturers Market Share by Revenue (2015-2020)3.2.3 Global Top 10 and Top 5 Companies by Stem Cell Equipment Revenue in 20193.3 Global Stem Cell Equipment Price by Manufacturers3.4 Mergers & Acquisitions, Expansion Plans

4 Stem Cell Equipment Production by Regions4.1 Global Stem Cell Equipment Historic Market Facts & Figures by Regions4.1.1 Global Top Stem Cell Equipment Regions by Production (2015-2020)4.1.2 Global Top Stem Cell Equipment Regions by Revenue (2015-2020)4.2 North America4.2.1 North America Stem Cell Equipment Production (2015-2020)4.2.2 North America Stem Cell Equipment Revenue (2015-2020)4.2.3 Key Players in North America4.2.4 North America Stem Cell Equipment Import & Export (2015-2020)4.3 Europe4.3.1 Europe Stem Cell Equipment Production (2015-2020)4.3.2 Europe Stem Cell Equipment Revenue (2015-2020)4.3.3 Key Players in Europe4.3.4 Europe Stem Cell Equipment Import & Export (2015-2020)4.4 China4.4.1 China Stem Cell Equipment Production (2015-2020)4.4.2 China Stem Cell Equipment Revenue (2015-2020)4.4.3 Key Players in China4.4.4 China Stem Cell Equipment Import & Export (2015-2020)4.5 Japan4.5.1 Japan Stem Cell Equipment Production (2015-2020)4.5.2 Japan Stem Cell Equipment Revenue (2015-2020)4.5.3 Key Players in Japan4.5.4 Japan Stem Cell Equipment Import & Export (2015-2020)

5 Stem Cell Equipment Consumption by Region5.1 Global Top Stem Cell Equipment Regions by Consumption5.1.1 Global Top Stem Cell Equipment Regions by Consumption (2015-2020)5.1.2 Global Top Stem Cell Equipment Regions Market Share by Consumption (2015-2020)5.2 North America5.2.1 North America Stem Cell Equipment Consumption by Application5.2.2 North America Stem Cell Equipment Consumption by Countries5.2.3 U.S.5.2.4 Canada5.3 Europe5.3.1 Europe Stem Cell Equipment Consumption by Application5.3.2 Europe Stem Cell Equipment Consumption by Countries5.3.3 Germany5.3.4 France5.3.5 U.K.5.3.6 Italy5.3.7 Russia5.4 Asia Pacific5.4.1 Asia Pacific Stem Cell Equipment Consumption by Application5.4.2 Asia Pacific Stem Cell Equipment Consumption by Regions5.4.3 China5.4.4 Japan5.4.5 South Korea5.4.6 India5.4.7 Australia5.4.8 Taiwan5.4.9 Indonesia5.4.10 Thailand5.4.11 Malaysia5.4.12 Philippines5.4.13 Vietnam5.5 Central & South America5.5.1 Central & South America Stem Cell Equipment Consumption by Application5.5.2 Central & South America Stem Cell Equipment Consumption by Country5.5.3 Mexico5.5.3 Brazil5.5.3 Argentina5.6 Middle East and Africa5.6.1 Middle East and Africa Stem Cell Equipment Consumption by Application5.6.2 Middle East and Africa Stem Cell Equipment Consumption by Countries5.6.3 Turkey5.6.4 Saudi Arabia5.6.5 U.A.E

6 Market Size by Type (2015-2026)6.1 Global Stem Cell Equipment Market Size by Type (2015-2020)6.1.1 Global Stem Cell Equipment Production by Type (2015-2020)6.1.2 Global Stem Cell Equipment Revenue by Type (2015-2020)6.1.3 Stem Cell Equipment Price by Type (2015-2020)6.2 Global Stem Cell Equipment Market Forecast by Type (2021-2026)6.2.1 Global Stem Cell Equipment Production Forecast by Type (2021-2026)6.2.2 Global Stem Cell Equipment Revenue Forecast by Type (2021-2026)6.2.3 Global Stem Cell Equipment Price Forecast by Type (2021-2026)6.3 Global Stem Cell Equipment Market Share by Price Tier (2015-2020): Low-End, Mid-Range and High-End

7 Market Size by Application (2015-2026)7.2.1 Global Stem Cell Equipment Consumption Historic Breakdown by Application (2015-2020)7.2.2 Global Stem Cell Equipment Consumption Forecast by Application (2021-2026)

8 Corporate Profiles8.1 Chart8.1.1 Chart Corporation Information8.1.2 Chart Overview and Its Total Revenue8.1.3 Chart Production Capacity and Supply, Price, Revenue and Gross Margin (2015-2020)8.1.4 Chart Product Description8.1.5 Chart Recent Development8.2 Worthington Industries8.2.1 Worthington Industries Corporation Information8.2.2 Worthington Industries Overview and Its Total Revenue8.2.3 Worthington Industries Production Capacity and Supply, Price, Revenue and Gross Margin (2015-2020)8.2.4 Worthington Industries Product Description8.2.5 Worthington Industries Recent Development8.3 Cesca Therapeutics8.3.1 Cesca Therapeutics Corporation Information8.3.2 Cesca Therapeutics Overview and Its Total Revenue8.3.3 Cesca Therapeutics Production Capacity and Supply, Price, Revenue and Gross Margin (2015-2020)8.3.4 Cesca Therapeutics Product Description8.3.5 Cesca Therapeutics Recent Development8.4 Shengjie Cryogenic Equipment8.4.1 Shengjie Cryogenic Equipment Corporation Information8.4.2 Shengjie Cryogenic Equipment Overview and Its Total Revenue8.4.3 Shengjie Cryogenic Equipment Production Capacity and Supply, Price, Revenue and Gross Margin (2015-2020)8.4.4 Shengjie Cryogenic Equipment Product Description8.4.5 Shengjie Cryogenic Equipment Recent Development8.5 Sichuan Mountain Vertical8.5.1 Sichuan Mountain Vertical Corporation Information8.5.2 Sichuan Mountain Vertical Overview and Its Total Revenue8.5.3 Sichuan Mountain Vertical Production Capacity and Supply, Price, Revenue and Gross Margin (2015-2020)8.5.4 Sichuan Mountain Vertical Product Description8.5.5 Sichuan Mountain Vertical Recent Development8.6 Qingdao Beol8.6.1 Qingdao Beol Corporation Information8.6.2 Qingdao Beol Overview and Its Total Revenue8.6.3 Qingdao Beol Production Capacity and Supply, Price, Revenue and Gross Margin (2015-2020)8.6.4 Qingdao Beol Product Description8.6.5 Qingdao Beol Recent Development

9 Production Forecasts by Regions9.1 Global Top Stem Cell Equipment Regions Forecast by Revenue (2021-2026)9.2 Global Top Stem Cell Equipment Regions Forecast by Production (2021-2026)9.3 Key Stem Cell Equipment Production Regions Forecast9.3.1 North America9.3.2 Europe9.3.3 China9.3.4 Japan

10 Stem Cell Equipment Consumption Forecast by Region10.1 Global Stem Cell Equipment Consumption Forecast by Region (2021-2026)10.2 North America Stem Cell Equipment Consumption Forecast by Region (2021-2026)10.3 Europe Stem Cell Equipment Consumption Forecast by Region (2021-2026)10.4 Asia Pacific Stem Cell Equipment Consumption Forecast by Region (2021-2026)10.5 Latin America Stem Cell Equipment Consumption Forecast by Region (2021-2026)10.6 Middle East and Africa Stem Cell Equipment Consumption Forecast by Region (2021-2026)11 Value Chain and Sales Channels Analysis11.1 Value Chain Analysis11.2 Sales Channels Analysis11.2.1 Stem Cell Equipment Sales Channels11.2.2 Stem Cell Equipment Distributors11.3 Stem Cell Equipment Customers12 Market Opportunities & Challenges, Risks and Influences Factors Analysis12.1 Market Opportunities and Drivers12.2 Market Challenges12.3 Market Risks/Restraints12.4 Porters Five Forces Analysis13 Key Finding in The Global Stem Cell Equipment Study14 Appendix14.1 Research Methodology14.1.1 Methodology/Research Approach14.1.2 Data Source14.2 Author Details14.3 Disclaimer

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In addition, the report categorizes product type and end uses as dynamic market segments that directly impact the growth potential and roadmap of the target market. The report highlights the core developments that are common to all regional hubs and their subsequent impact on the holistic growth path of the Stem Cell Assay Depth market worldwide. Other valuable aspects of the report are the market development history, various marketing channels, supplier analysis, potential buyers and the analysis of the markets industrial chain.

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Table of Content

1 Introduction of Stem Cell Assay Depth Market

1.1 Overview of the Market1.2 Scope of Report1.3 Assumptions

2 Executive Summary

3 Research Methodology of Verified Market Research

3.1 Data Mining3.2 Validation3.3 Primary Interviews3.4 List of Data Sources

4 Stem Cell Assay Depth Market Outlook

4.1 Overview4.2 Market Dynamics4.2.1 Drivers4.2.2 Restraints4.2.3 Opportunities4.3 Porters Five Force Model4.4 Value Chain Analysis

5 Stem Cell Assay Depth Market, By Deployment Model

5.1 Overview

6 Stem Cell Assay Depth Market, By Solution

6.1 Overview

7 Stem Cell Assay Depth Market, By Vertical

7.1 Overview

8 Stem Cell Assay Depth Market, By Geography

8.1 Overview8.2 North America8.2.1 U.S.8.2.2 Canada8.2.3 Mexico8.3 Europe8.3.1 Germany8.3.2 U.K.8.3.3 France8.3.4 Rest of Europe8.4 Asia Pacific8.4.1 China8.4.2 Japan8.4.3 India8.4.4 Rest of Asia Pacific8.5 Rest of the World8.5.1 Latin America8.5.2 Middle East

9 Stem Cell Assay Depth Market Competitive Landscape

9.1 Overview9.2 Company Market Ranking9.3 Key Development Strategies

10 Company Profiles

10.1.1 Overview10.1.2 Financial Performance10.1.3 Product Outlook10.1.4 Key Developments

11 Appendix

11.1 Related Research

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CC-92480, a novel cereblon E3 ligase modulator agent, in combination with dexamethasone appeared safe and active in patients with heavily pretreated relapsed or refractory multiple myeloma, according to data presented during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.

CC-92480, as a novel CELMoD (cereblon E3 ligase modulator) agent, has promising activity preclinically, and this has been successfully translated to the clinic with a manageable safety profile in patients with heavily pretreated RRMM, meaning disease that has been resistant to previous treatment or has recurred, Dr. Paul G. Richardson, clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, said in his presentation.

A CELMoD is a targeted drug that inhibits the activity of the protein cereblon, setting off a chain reaction that modifies immune response and also directly fights cancer.

To evaluate the maximum tolerated dose, recommended phase 2 dose, safety and tolerability of CC-92480 plus the steroid dexamethasone, 76 patients (median age, 66 years; range, 44-78) with heavily pretreated RRMM were enrolled in the phase 1 dose-escalation study.

Patients within the study had received a median of six prior treatment regimens. All patients had received a previous proteasome inhibitor, 97.4% received Revlimid (lenalidomide), 92.1% received Pomalyst (pomalidomide), 75% received anti-CD38 antibodies and 76.3% had received autologous stem cell transplantation.

For patients to be eligible to be in the study, they had to have experienced disease progression on or within 60 days of their last therapy, as well as resistance or intolerance to other multiple myeloma therapies, or ineligibility for them.

The overall response rate (ORR, meaning the proportion of patients who had a partial or complete response to treatment) was 21.1% among the overall patient population with one complete response, six very good partial responses, nine partial responses and four minimal responses.The efficacy of the combination was dependent on the dose level and treatment schedule.

Patients received CC-92480 on either a continuous or intensive dosing schedule. Treatment began at 0.1 milligrams (mg) and was escalated up to 1 mg the maximum tolerated dose per day for 10 out of 14 days during a 28-day cycle in the continuous schedule cohorts.

However, after noting that patients needed longer continuous breaks to recover their neutrophil counts, researchers switched to a 21 out of 28-day schedule.

Patients on the intensive schedule received 0.2 mg of study drug, which was escalated up to 0.8 mg twice a day, administered three out of 14 days twice a month. However, that schedule was eventually changed to 1.6 mg to 2 mg once daily for seven out of 14 days twice a month.

The ORR was 40% in patients treated with the 10 out of 14-day continuous dosing schedule and 54.5% in those treated in a 21 out of 28-day continuous schedule.

The most common treatment-emergent side effects of any grade across the study population included a deficiency of neutrophils in the blood (73.7%), infections (71%), anemia (55.3%), a deficiency of platelets in the blood (43.4%) and fatigue (38.2%). Dose-limiting side effects among the different patient groups were mostly associated with neutrophil deficiency.

Dose reduction of CC-92480 occurred in 22.4% of patients, and there were no discontinuations due to treatment-related side effects.

At the time of the data cutoff, 25 patients were still receiving therapy. Progressive disease caused 51.3% of patients to discontinue treatment. Five patients died during the study; however, no deaths were considered related to the study drug.

Especially important for our patients (is that) we have seen really promising activity at therapeutic doses in patients who are truly refractory not only to pomalidomide, but also to proteasome inhibition and monoclonal antibody therapy in the setting of extramedullary disease, Richardson said. Going forward, there is now a phase 1/2 study evaluating the safety and efficacy of (CC-92480) in combination with other standard treatments in patients with relapsed/refractory multiple myeloma, and these results will hopefully validate what we have seen to date.

A version of this story originally appeared on OncLive as CC-92480 Shows Encouraging Efficacy in First-in-Human Study for R/R Multiple Myeloma.

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First-in-Human Trial of Novel Therapy Shows Promising Results in Relapsed/Refractory Multiple Myeloma - Curetoday.com

Los Angeles, United State: Complete study of the global Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies market is carried out by the analysts in this report, taking into consideration key factors like drivers, challenges, recent trends, opportunities, advancements, and competitive landscape. This report offers a clear understanding of the present as well as future scenario of the global Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies industry. Research techniques like PESTLE and Porters Five Forces analysis have been deployed by the researchers. They have also provided accurate data on Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies production, capacity, price, cost, margin, and revenue to help the players gain a clear understanding into the overall existing and future market situation.

The research study includes great insights about critical market dynamics, including drivers, restraints, trends, and opportunities. It also includes various types of market analysis such as competitive analysis, manufacturing cost analysis, manufacturing process analysis, price analysis, and analysis of market influence factors. It is a complete study on the global Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies market that can be used as a set of effective guidelines for ensuring strong growth in the coming years. It caters to all types of interested parties, viz. stakeholders, market participants, investors, market researchers, and other individuals associated with the Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies business.

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It is important for every market participant to be familiar with the competitive scenario in the global Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies industry. In order to fulfil the requirements, the industry analysts have evaluated the strategic activities of the competitors to help the key players strengthen their foothold in the market and increase their competitiveness.

Key Players Mentioned in the Global Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Research Report: , Orange County Hair Restoration Center, Hair Sciences Center of Colorado, Anderson Center for Hair, Evolution Hair Loss Institute, Savola Aesthetic Dermatology Center, Virginia Surgical Center, Hair Transplant Institute of Miami, Colorado Surgical Center & Hair Institute Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies

Global Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Segmentation by Product:, Platelet Rich Plasma Injections, Stem Cell Therapy Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies

Global Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Segmentation by Application: Dermatology Clinics, Hospitals

The report has classified the global Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies industry into segments including product type and application. Every segment is evaluated based on growth rate and share. Besides, the analysts have studied the potential regions that may prove rewarding for the Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies manufcaturers in the coming years. The regional analysis includes reliable predictions on value and volume, thereby helping market players to gain deep insights into the overall Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies industry.

Additionally, the industry analysts have studied key regions including North America, Europe, Asia Pacific, Latin America, and Middle East and Africa, along with their respective countries. Here, they have given a clear-cut understanding of the present and future situations of the global Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies industry in key regions. This will help the key players to focus on the lucrative regional markets.

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Table od Content

1 Report Overview1.1 Study Scope1.2 Key Market Segments1.3 Players Covered: Ranking by Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Revenue1.4 Market Analysis by Type1.4.1 Global Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Size Growth Rate by Type: 2020 VS 20261.4.2 Platelet Rich Plasma Injections1.4.3 Stem Cell Therapy1.5 Market by Application1.5.1 Global Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Share by Application: 2020 VS 20261.5.2 Dermatology Clinics1.5.3 Hospitals1.6 Coronavirus Disease 2019 (Covid-19): Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Industry Impact1.6.1 How the Covid-19 is Affecting the Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Industry1.6.1.1 Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Business Impact Assessment Covid-191.6.1.2 Supply Chain Challenges1.6.1.3 COVID-19s Impact On Crude Oil and Refined Products1.6.2 Market Trends and Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Potential Opportunities in the COVID-19 Landscape1.6.3 Measures / Proposal against Covid-191.6.3.1 Government Measures to Combat Covid-19 Impact1.6.3.2 Proposal for Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Players to Combat Covid-19 Impact1.7 Study Objectives1.8 Years Considered 2 Global Growth Trends by Regions2.1 Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Perspective (2015-2026)2.2 Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Growth Trends by Regions2.2.1 Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Size by Regions: 2015 VS 2020 VS 20262.2.2 Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Historic Market Share by Regions (2015-2020)2.2.3 Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Forecasted Market Size by Regions (2021-2026)2.3 Industry Trends and Growth Strategy2.3.1 Market Top Trends2.3.2 Market Drivers2.3.3 Market Challenges2.3.4 Porters Five Forces Analysis2.3.5 Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Growth Strategy2.3.6 Primary Interviews with Key Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Players (Opinion Leaders) 3 Competition Landscape by Key Players3.1 Global Top Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Players by Market Size3.1.1 Global Top Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Players by Revenue (2015-2020)3.1.2 Global Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Revenue Market Share by Players (2015-2020)3.1.3 Global Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Share by Company Type (Tier 1, Tier 2 and Tier 3)3.2 Global Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Concentration Ratio3.2.1 Global Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Concentration Ratio (CR5 and HHI)3.2.2 Global Top 10 and Top 5 Companies by Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Revenue in 20193.3 Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Key Players Head office and Area Served3.4 Key Players Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Product Solution and Service3.5 Date of Enter into Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market3.6 Mergers & Acquisitions, Expansion Plans 4 Breakdown Data by Type (2015-2026)4.1 Global Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Historic Market Size by Type (2015-2020)4.2 Global Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Forecasted Market Size by Type (2021-2026) 5 Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Breakdown Data by Application (2015-2026)5.1 Global Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Size by Application (2015-2020)5.2 Global Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Forecasted Market Size by Application (2021-2026) 6 North America6.1 North America Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Size (2015-2020)6.2 Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Key Players in North America (2019-2020)6.3 North America Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Size by Type (2015-2020)6.4 North America Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Size by Application (2015-2020) 7 Europe7.1 Europe Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Size (2015-2020)7.2 Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Key Players in Europe (2019-2020)7.3 Europe Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Size by Type (2015-2020)7.4 Europe Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Size by Application (2015-2020) 8 China8.1 China Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Size (2015-2020)8.2 Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Key Players in China (2019-2020)8.3 China Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Size by Type (2015-2020)8.4 China Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Size by Application (2015-2020) 9 Japan9.1 Japan Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Size (2015-2020)9.2 Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Key Players in Japan (2019-2020)9.3 Japan Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Size by Type (2015-2020)9.4 Japan Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Size by Application (2015-2020) 10 Southeast Asia10.1 Southeast Asia Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Size (2015-2020)10.2 Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Key Players in Southeast Asia (2019-2020)10.3 Southeast Asia Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Size by Type (2015-2020)10.4 Southeast Asia Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Size by Application (2015-2020) 11 India11.1 India Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Size (2015-2020)11.2 Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Key Players in India (2019-2020)11.3 India Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Size by Type (2015-2020)11.4 India Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Size by Application (2015-2020) 12 Central & South America12.1 Central & South America Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Size (2015-2020)12.2 Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Key Players in Central & South America (2019-2020)12.3 Central & South America Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Size by Type (2015-2020)12.4 Central & South America Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market Size by Application (2015-2020) 13 Key Players Profiles13.1 Orange County Hair Restoration Center13.1.1 Orange County Hair Restoration Center Company Details13.1.2 Orange County Hair Restoration Center Business Overview and Its Total Revenue13.1.3 Orange County Hair Restoration Center Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Introduction13.1.4 Orange County Hair Restoration Center Revenue in Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Business (2015-2020))13.1.5 Orange County Hair Restoration Center Recent Development13.2 Hair Sciences Center of Colorado13.2.1 Hair Sciences Center of Colorado Company Details13.2.2 Hair Sciences Center of Colorado Business Overview and Its Total Revenue13.2.3 Hair Sciences Center of Colorado Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Introduction13.2.4 Hair Sciences Center of Colorado Revenue in Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Business (2015-2020)13.2.5 Hair Sciences Center of Colorado Recent Development13.3 Anderson Center for Hair13.3.1 Anderson Center for Hair Company Details13.3.2 Anderson Center for Hair Business Overview and Its Total Revenue13.3.3 Anderson Center for Hair Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Introduction13.3.4 Anderson Center for Hair Revenue in Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Business (2015-2020)13.3.5 Anderson Center for Hair Recent Development13.4 Evolution Hair Loss Institute13.4.1 Evolution Hair Loss Institute Company Details13.4.2 Evolution Hair Loss Institute Business Overview and Its Total Revenue13.4.3 Evolution Hair Loss Institute Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Introduction13.4.4 Evolution Hair Loss Institute Revenue in Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Business (2015-2020)13.4.5 Evolution Hair Loss Institute Recent Development13.5 Savola Aesthetic Dermatology Center13.5.1 Savola Aesthetic Dermatology Center Company Details13.5.2 Savola Aesthetic Dermatology Center Business Overview and Its Total Revenue13.5.3 Savola Aesthetic Dermatology Center Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Introduction13.5.4 Savola Aesthetic Dermatology Center Revenue in Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Business (2015-2020)13.5.5 Savola Aesthetic Dermatology Center Recent Development13.6 Virginia Surgical Center13.6.1 Virginia Surgical Center Company Details13.6.2 Virginia Surgical Center Business Overview and Its Total Revenue13.6.3 Virginia Surgical Center Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Introduction13.6.4 Virginia Surgical Center Revenue in Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Business (2015-2020)13.6.5 Virginia Surgical Center Recent Development13.7 Hair Transplant Institute of Miami13.7.1 Hair Transplant Institute of Miami Company Details13.7.2 Hair Transplant Institute of Miami Business Overview and Its Total Revenue13.7.3 Hair Transplant Institute of Miami Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Introduction13.7.4 Hair Transplant Institute of Miami Revenue in Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Business (2015-2020)13.7.5 Hair Transplant Institute of Miami Recent Development13.8 Colorado Surgical Center & Hair Institute13.8.1 Colorado Surgical Center & Hair Institute Company Details13.8.2 Colorado Surgical Center & Hair Institute Business Overview and Its Total Revenue13.8.3 Colorado Surgical Center & Hair Institute Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Introduction13.8.4 Colorado Surgical Center & Hair Institute Revenue in Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Business (2015-2020)13.8.5 Colorado Surgical Center & Hair Institute Recent Development 14 Analysts Viewpoints/Conclusions 15 Appendix15.1 Research Methodology15.1.1 Methodology/Research Approach15.1.2 Data Source15.2 Disclaimer15.3 Author Details

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Stem Cell and Platelet Rich Plasma (PRP) Alopecia Therapies Market In Depth Research with Industry Driving Factors, Consumer Behaviour Analysis,...

A report, added to the extensive database of verified Market Research titled Stem Cell Alopecia Treatment Market 2020 by Manufacturer, Region, Type and Application, Forecast up to 2026, is intended to highlight first-hand documentation of all the best implementations in the industry. The report contains an in-depth analysis of current and future market trends, segmentation, industrial opportunities and the future market scenario, taking into account the forecast years 2020 to 2026. It contains extremely important details on the key players in the Stem Cell Alopecia Treatment market as well as growth-oriented practices, that they normally use. The report examines a number of growth drivers and limiting factors. The key forecast information by region, type and application with sales and revenue from 2020 to 2026 is included in this report.

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Top 10 Companies in the Stem Cell Alopecia Treatment Market Research Report:

Competitive landscape:

The report examines the major players, including the profiles of the major players in the market with a significant global and / or regional presence, combined with their information such as related companies, downstream buyers, upstream suppliers, market position, historical background and top competitors based on the Sales with sales contact information.

Regional Description:

The Stem Cell Alopecia Treatment market was analyzed and a proper survey of the market was carried out based on all regions of the world. The regions listed in the report include: North America (United States, Canada, and Mexico), Europe (Germany, France, United Kingdom, Russia, and Italy), Asia-Pacific (China, Japan, Korea, India, and Southeast Asia), South America (Brazil, Argentina , Colombia etc.), Middle East and Africa (Saudi Arabia, United Arab Emirates, Egypt, Nigeria and South Africa). All these regions have been studied in detail and the prevailing trends and different possibilities are also mentioned in the market report.

Sales and sales broken down by application:

Sales and sales divided by type:

In addition, the report categorizes product type and end uses as dynamic market segments that directly impact the growth potential and roadmap of the target market. The report highlights the core developments that are common to all regional hubs and their subsequent impact on the holistic growth path of the Stem Cell Alopecia Treatment market worldwide. Other valuable aspects of the report are the market development history, various marketing channels, supplier analysis, potential buyers and the analysis of the markets industrial chain.

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Table of Content

1 Introduction of Stem Cell Alopecia Treatment Market

1.1 Overview of the Market1.2 Scope of Report1.3 Assumptions

2 Executive Summary

3 Research Methodology of Verified Market Research

3.1 Data Mining3.2 Validation3.3 Primary Interviews3.4 List of Data Sources

4 Stem Cell Alopecia Treatment Market Outlook

4.1 Overview4.2 Market Dynamics4.2.1 Drivers4.2.2 Restraints4.2.3 Opportunities4.3 Porters Five Force Model4.4 Value Chain Analysis

5 Stem Cell Alopecia Treatment Market, By Deployment Model

5.1 Overview

6 Stem Cell Alopecia Treatment Market, By Solution

6.1 Overview

7 Stem Cell Alopecia Treatment Market, By Vertical

7.1 Overview

8 Stem Cell Alopecia Treatment Market, By Geography

8.1 Overview8.2 North America8.2.1 U.S.8.2.2 Canada8.2.3 Mexico8.3 Europe8.3.1 Germany8.3.2 U.K.8.3.3 France8.3.4 Rest of Europe8.4 Asia Pacific8.4.1 China8.4.2 Japan8.4.3 India8.4.4 Rest of Asia Pacific8.5 Rest of the World8.5.1 Latin America8.5.2 Middle East

9 Stem Cell Alopecia Treatment Market Competitive Landscape

9.1 Overview9.2 Company Market Ranking9.3 Key Development Strategies

10 Company Profiles

10.1.1 Overview10.1.2 Financial Performance10.1.3 Product Outlook10.1.4 Key Developments

11 Appendix

11.1 Related Research

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Impact of Covid-19 Outbreak on Stem Cell Alopecia Treatment Market 2020 Trends, Growth Opportunities, Demand, Application, Top Companies and Industry...

Mike Tyson has attributed his incredible body transformation to stem cell therapy and a rigid vegan diet.

The youngest world heavyweight champion in history ballooned to more than 300lbs in weight at his heaviest almost a decade ago.

However, after drastically changing his diet and implementing revolutionary reparative medication, Iron Mike is looking more streamlined and more devastating than ever.

Tyson is reportedly considering making a return to the squared circle at the age of 53, with an announcement on his opponent expected this week.

Whilst training with UFC legends Vitor Belfort and Henry Cejudo, the former undisputed heavyweight champion displayed a significantly more shredded physique.

Prior to officially announcing his desire to return, Tyson was asked by rapper LL Cool J how he would get fighting fit in just six to eight weeks.

He told Rock the Bells Radio show on SiriusXM: Really I would just change my diet and just do cardio work. Cardio has to start, you have to have your endurance to go and do the process of training.

Mike Tyson

So something to do is get in cardio, I would try and get two hours of cardio a day, make sure you get that stuff in. Youre gonna make sure youre eating the right food.

For me its almost like slave food. Doing what you hate to do but doing it like its nothing. Getting up when you dont want to get up. Thats what it is. Its becoming a slave to life.

People think a slave to life is just enjoying drugs and living your life. Being a slave to life means being the best person you can be, being the best you can possibly be, and when you are at the best you can possibly be is when you no longer exist and nobody talks about you. Thats when youre at your best.

Tyson continued: My mind wouldnt belong to me. My mind would belong to somebody that disliked me enough to break my soul, and I would give them my mind for that period of time.

Six weeks of this and Id be in the best shape Ive ever dreamed of being in. As a matter of fact, Im going through that process right now. And you know what else I did, I did stem-cell research.

Stem-cell research (also known as regenerative medicine) promotes the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives.

It is the latest advancement in organ transplantation and uses cells instead of donor organs, which are limited in supply.

After LL Cool J asked if that meant Tysons white blood cells had been spun and then put back in, Tyson continued: Yes. As they took the blood it was red and when it came back it was almost transfluid [sic], I could almost see through the blood, and then they injected it in me. And Ive been weird ever since, Ive got to get balanced now.

Getty Images - Getty

The necessity to repair the former heavyweight champion was caused by the excessive weight gain following his retirement in 2005 and his hedonistic lifestyle.

Excessive cocaine abuse left the heavyweight in a serious state of bother and led him to adopt a vegan lifestyle.

He told Totally Vegan Buzz: I was so congested from all the drugs and bad cocaine, I could hardly breathe. Tyson also revealed in the interview, I had high blood pressure, was almost dying, and had arthritis.

During aninterviewwith Oprah Winfrey in 2013, Tysoncredits his plant-based diet for saving his life.

Getty Images

He said: Well, my life is different today because I have stability in my life. Im not on drugs.

Im not out on the streets or in clubs and everything in my life that I do now is structured around the development of my life and my family. I lost weight.

I dropped over 100lbs and I just felt like changing my life, doing something different and I became a vegan.

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Vegan diet, intense cardio and stem cell therapy How Mike Tyson managed to get ripped at 53 as boxing c - talkSPORT.com

ORLANDO, Fla.--(BUSINESS WIRE)--Hesperos Inc., pioneers of the Human-on-a-Chip in vitro system, today announced a new peer-reviewed publication that describes how the companys functional Human-on-a-Chip system can be used as a drug discovery platform to identify therapeutic interventions targeting the preclinical stages of Alzheimers disease (AD) and mild cognitive impairment (MCI). The manuscript, titled A human induced pluripotent stem cell-derived cortical neuron human-on-a-chip system to study A42 and tau-induced pathophysiological effects on long-term potentiation, was published this week in Alzheimer's & Dementia: Translational Research & Clinical Interventions. The work was conducted in collaboration with the University of Central Florida and with David G. Morgan, Ph.D., Professor of Translational Neuroscience at Michigan State University, and expert in AD pathology.

To date, more than 100 potential therapeutics in development for AD have been abandoned or failed during clinical trials. These therapeutics relied on research conducted in preclinical animal studies, which often are unable to accurately capture the full spectrum of the human disease phenotype, including differences in drug metabolism and excretion between humans and animals. Therefore, there is a need for human models, especially those that accurately recapitulate the functional impairments during the preclinical phases of AD and MCI.

Hesperos offers a breakthrough technology that provides a human cell-based assay based on cognitive function metrics to evaluate drugs designed to restore cognition at early stages of the Alzheimers continuum, said Dr. Morgan. This system can serve as a novel drug discovery platform to identify compounds that rescue or alleviate the initial neuronal deficits caused by A1-42 and/or tau oligomers, which is a main focus of clinical trials.

In 2018, Hesperos received a Phase I Small Business Innovation Research (SBIR) grant from the National Institute on Aging (NIA) division within the US National Institutes of Health (NIH) to help create a new multi-organ human-on-a-chip model for testing AD drugs. Research conducted under this grant included a study to assess therapeutic interventions based on functional changes in neurons, not neuronal death.

In the recent Alzheimer's & Dementia publication, Hesperos describes its in vitro human induced pluripotent stem cell (iPSC)-derived cortical neuron human-on-a-chip system for the evaluation of neuron morphology and function after exposure to toxic A and tau oligomers as well as brain extracts from AD transgenic mouse models.

Researchers are now focusing on biomarker development and therapeutic intervention before symptoms arise in AD and MCI, said James Hickman, Ph.D., Chief Scientist at Hesperos and Professor at the University of Central Florida. By studying functional disruption without extensive cell loss, we now have a screening methodology for drugs that could potentially evaluate therapeutic efficacy even before the neurodegeneration in MCI and AD occurs.

The researchers found that compared to controls, treatment with toxic A and tau oligomers or brain extracts on the iPSC cortical neurons significantly impaired information processing as demonstrated by reduction in high-frequency stimulation-induced long-term potentiation (LTP), a process that is thought to underlie memory formation and learning. Additionally, oligomer and brain extract exposure led to dysfunction in iPSC cortical neuron electrophysiological activity, including decreases in ion current and action potential firing.

While exposure to the toxic oligomers and brain extracts caused morphological defects in the iPSC cortical neurons, there was no significant loss in cell viability.

Clinical success for AD therapies has been challenging since preclinical animal studies often do not translate to humans, said Michael L. Shuler, Ph.D., Chief Executive Officer of Hesperos. With our recent study, we are now one step closer in developing an AD multi-organ model to better evaluate drug metabolism in the liver, penetration through the blood-brain barrier and the effects on neuronal cells.

About Alzheimers Disease/Preclinical Stage AD

AD is a progressive disease that is characterized by memory loss and deterioration of cognitive function. Preclinical AD is the first stage of the disease, and it begins long before any symptoms become apparent. It is thought that symptoms do not manifest until there is a significant death of neuronal cells, which is caused by the aggregation of toxic amyloid beta (A) and tau oligomers, typically during the earliest stages of the disease. Unfortunately, treatment after the diagnosis of MCI may be too late to reverse or modify disease progression.

To read the full manuscript, please visit https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/trc2.12029.

About Hesperos

Hesperos, Inc. is a leading provider of Human-on-a-Chip microfluidic systems to characterize an individuals biology. Founders Michael L. Shuler and James J. Hickman have been at the forefront of every major scientific discovery in this realm, from individual organ-on-a-chip constructs to fully functional, interconnected multi-organ systems. With a mission to revolutionize toxicology testing as well as efficacy evaluation for drug discovery, the company has created pumpless platforms with serum-free cellular mediums that allow multi-organ system communication and integrated computational PKPD modeling of live physiological responses utilizing functional readouts from neurons, cardiac, muscle, barrier tissues and neuromuscular junctions as well as responses from liver, pancreas and barrier tissues. Created from human stem cells, the fully human systems are the first in vitro solutions to accurately predict in vivo functions without the use of animal models. More information is available at http://www.hesperosinc.com.

Hesperos and Human-on-a-Chip are trademarks of Hesperos Inc. All other brands may be trademarks of their respective holders.

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Hesperos Human-on-a-Chip System Used to Model Preclinical Stages of Alzheimer's Disease and Mild Cognitive Impairment - Business Wire

Acute lung injury (ALI) is a devastating disease process involving pulmonary edema and atelectasis caused by capillary membrane injury [1]. The main clinical manifestation is the acute onset of hypoxic respiratory failure, which can subsequently trigger a cascade of serious complications and even death [2]. Thus, ALI causes a considerable financial burden for health care systems throughout the world. ALI can result from various causes, including multiple traumas, large-volume blood transfusions, and bacterial and viral infections [2, 3]. A variety of viruses, including influenza virus, coronavirus (CoV), adenovirus, cytomegalovirus (CMV), and respiratory syncytial virus (RSV), are associated with ALI [4]. Importantly, most viruses, whose hosts are various animal species, can cause severe and rapidly spreading human infections. In the early 2000s, several outbreaks of influenza virus and CoV emerged, causing human respiratory and intestinal diseases worldwide, including the more recent SARS-CoV-2 infection [5,6,7]. To date, SARS-CoV-2 has affected more than 80,000 people, causing nearly 3300 deaths in China and more than 1,800,000 people, causing nearly 110,000 deaths all over the world (http://2019ncov.chinacdc.cn/2019-nCoV/).

Infectious respiratory diseases caused by different viruses are associated with similar respiratory symptoms ranging from the common cold to severe acute respiratory syndrome [8]. This makes the clinical distinction between different agents involved in infection very difficult [8, 9]. Currently, the clinical experience mainly includes antibacterial and antiviral drug treatment derived from handling several outbreaks of influenza virus and human CoVs. Numerous agents have been identified to inhibit the entry and/or replication of these viruses in cell culture or animal models [10]. Although these antiviral drugs can effectively prevent and eliminate the virus, the full recovery from pneumonia and ALI depends on the resistance of the patient. Recently, stem cell-based therapy has become a potential approved tool for the treatment of virus-induced lung injury [11,12,13]. Here, we will give a brief overview of influenza virus and CoVs and then present the cell-based therapeutic options for lung injury caused by different kinds of viruses.

Influenza virus and human CoV are the two most threatening viruses for infectious lung injury [14]. These pathogens can be transmitted through direct or indirect physical contact, droplets, or aerosols, with increasing evidence suggesting that airborne transmission, including via droplets or aerosols, enhances the efficiency of viral transmission among humans and causes uncontrolled infectious disease [15]. Throughout human history, outbreaks and occasional pandemics caused by influenza virus and CoV have led to approximately hundreds of millions of deaths worldwide [16].

Influenza virus is a well-known human pathogen that has a negative-sense RNA genome [17]. According to its distinct antigenic properties, the influenza virus can be divided into 4 subtypes, types A, B, C, and D. Influenza A virus (IAV) lineages in animal populations cause economically important respiratory disease. Little is known about the other human influenza virus types B, C, and D [18]. Further subtypes are characterized by the genetic and antigenic properties of the hemagglutinin (HA) and neuraminidase (NA) glycoproteins [19]. Sporadic and seasonal infections in swine with avian influenza viruses of various subtypes have been reported. The most recent human pandemic virusesH1N1 from swine and H5N1 from aviancause severe respiratory tract disease and lung injury in humans [20, 21].

CoVs, a large family of single-stranded RNA viruses, typically affect the respiratory tract of mammals, including humans. CoVs are further divided into four genera: alpha-, beta-, gamma-, and delta-CoVs. Alpha- and beta-CoVs can infect mammals, and gamma- and delta-CoVs tend to infect birds, but some of these viruses can also be transmitted to mammals [22]. Human CoVs were considered relatively harmless respiratory pathogens in the past. Infections with the human CoV strains 229E, OC43, NL63, and HKU1 usually result in mild respiratory illness, such as the common cold [23]. In contrast, the CoV responsible for the 2002 severe acute respiratory syndrome (SARS-CoV), the 2012 Middle East respiratory syndrome CoV (MERS-CoV), and, more recently, the SARS-CoV-2 have received global attention owing to their genetic variation and rapid spread in human populations [5,6,7].

Usually, the influenza virus can enter the columnar epithelial cells of the respiratory tract, such as the trachea, bronchi, and bronchioles. Subsequently, the influenza virus begins to replicate for an asymptomatic period of time and then migrate to the lung tissue to cause acute lung and respiratory injury [24]. Similar to those with influenza virus infection, patients with SARS, MERS, or SARS-CoV-2 present with various clinical features, ranging from asymptomatic or mild respiratory illness to severe ALI, even with multiple organ failure [5,6,7]. The pathogenesis of ALI caused by influenza virus and human CoV is often associated with rapid viral replication, marked inflammatory cell infiltration, and elevated proinflammatory cytokine/chemokine responses [25]. Interestingly, in IAV- and human CoV-infected individuals, the pulmonary pathology always involves diffuse alveolar damage, but viral RNA is present in only a subset of patients [26]. Some studies suggest that an overly exaggerated immune response, rather than uncontrolled viral spread, is the primary cause in fatal cases caused by virus infection [27]. Several immune cell types have been found to contribute to damaging host responses, providing novel approaches for therapeutic intervention [28].

IAV infection, the most common cause of viral pneumonia, causes substantial seasonal and pandemic morbidity and mortality [29]. Currently, antiviral drugs are the primary treatment strategy for influenza-induced pneumonia. However, antiviral drugs cannot repair damaged lung cells. Here, we summarize the present studies of stem cell therapy for influenza virus-induced lung injury.

Mesenchymal stem/stromal cells (MSCs) constitute a heterogeneous subset of stromal regenerative cells that can be harvested from several adult tissue types, including bone marrow, umbilical cord, adipose, and endometrium [30]. They retain the expression of the markers CD29, CD73, CD90, and CD105 and have a rapid proliferation rate, low immunogenicity, and low tumorigenicity [30]. MSCs also have self-renewal and multidifferentiation capabilities and exert immunomodulatory and tissue repair effects by secreting trophic factors, cytokines, and chemokines [31]. Due to these beneficial biological properties, MSCs and their derivatives are attractive as cellular therapies for various inflammatory diseases, including virus-induced lung injury.

Several studies on IAV-infected animal models have shown the beneficial effects of the administration of different tissue-derived MSCs [32,33,34,35]. H5N1 virus infection reduces alveolar fluid clearance (AFC) and enhances alveolar protein permeability (APP) in human alveolar epithelial cells, which can be inhibited by coculture with human bone marrow-derived MSCs (BMSCs) [32]. Mechanistically, this process can be mediated by human BMSC secreted angiopoietin-1 (Ang1) and keratinocyte growth factor (KGF) [32]. Moreover, in vivo experiments have shown that human BMSCs have a significant anti-inflammatory effect by increasing the number of M2 macrophages and releasing various cytokines and chemokines, such as interleukin (IL)-1, IL-4, IL-6, IL-8, and IL-17 [32]. Similar anti-inflammatory effects have been achieved in another virus-induced lung injury model. The intravenous injection of mouse BMSCs into H9N2 virus-infected mice significantly attenuates H9N2 virus-induced pulmonary inflammation by reducing chemokine (GM-CSF, MCP-1, KC, MIP-1, and MIG) and proinflammatory cytokine (IL-1, IL-6, TNF-, and IFN-) levels, as well as reducing inflammatory cell recruitment into the lungs [33]. Another study on human BMSCs cocultured with CD8+ T cells showed that MSCs inhibit the proliferation of virus-specific CD8+ T cells and the release of IFN- by specific CD8+ T cells [36].

In addition, human umbilical cord-derived MSCs (UC-MSCs) were found to have a similar effect as BMSCs on AFC, APP, and inflammation by secreting growth factors, including Ang1 and hepatocyte growth factor (HGF), in an in vitro lung injury model induced by H5N1 virus [34]. UC-MSCs also promote lung injury mouse survival, increase the body weight, and decreased the APP levels and inflammation in vivo [34]. Unlike Ang1, KGF, and HGF mentioned above, basic fibroblast growth factor 2 (FGF2) plays an important role in lung injury therapy via immunoregulation. The administration of the recombinant FGF2 protein improves H1N1-induced mouse lung injury and promotes the survival of infected mice by recruiting and activating neutrophils via the FGFR2-PI3K-AKT-NFB signaling pathway [37]. FGF2-overexpressing MSCs have an enhanced therapeutic effect on lipopolysaccharide-induced ALI, as assessed by the proinflammatory factor level, neutrophil quantity, and histopathological index of the lung [38].

MSCs secrete various soluble factors and extracellular vesicles (EVs), which carry lipids, proteins, DNA, mRNA, microRNAs, small RNAs, and organelles. These biologically active components can be transferred to recipient cells to exert anti-inflammatory, antiapoptotic, and tissue regeneration functions [39]. EVs isolated from conditioned medium of pig BMSCs have been demonstrated to have anti-apoptosis, anti-inflammation, and antiviral replication functions in H1N1-affected lung epithelial cells and alleviate H1N1-induced lung injury in pigs [35]. Moreover, the preincubation of EVs with RNase abrogates their anti-influenza activity, suggesting that the anti-influenza activity of EVs is due to the transfer of RNAs from EVs to epithelial cells [35]. Exosomes are a subset of EVs that are 50200nm in diameter and positive for CD63 and CD81 [40]. Exosomes isolated from the conditioned medium of UC-MSCs restore the impaired AFC and decreased APP in alveolar epithelial cells affected by H5N1 virus [34]. In addition, the ability of UC-MSCs to increase AFC is superior to that of exosomes, which indicates that other components secreted by UC-MSCs have synergistic effects with exosomes [34].

Despite accumulating evidence demonstrating the therapeutic effects of MSC administration in various preclinical models of lung injury, some studies have shown contrasting results. Darwish and colleagues proved that neither the prophylactic nor therapeutic administration of murine or human BMSCs could decrease pulmonary inflammation or prevent the progression of ALI in H1N1 virus-infected mice [41]. In addition, combining MSC administration with the antiviral agent oseltamivir was also found to be ineffective [41]. Similar negative results were obtained in another preclinical study. Murine or human BMSCs were administered intravenously to H1N1-induced ARDS mice [42]. Although murine BMSCs prevented influenza-induced thrombocytosis and caused a modest reduction in lung viral load, murine or human BMSCs failed to improve influenza-mediated lung injury as assessed by weight loss, the lung water content, and bronchoalveolar lavage inflammation and histology, which is consistent with Darwishs findings [42]. However, the mild reduction in viral load observed in response to murine BMSC treatment suggests that, on balance, MSCs are mildly immunostimulatory in this model [42]. Although there are some controversial incidents in preclinical research, the transplant of menstrual-blood-derived MSCs into patients with H7N9-induced ARDS was conducted at a single center through an open-label clinical trial (http://www.chictr.org.cn/). MSC transplantation significantly lowered the mortality and did not result in harmful effects in the bodies of the patients [43]. This clinic study suggests that MSCs significantly improve the survival rate of influenza virus-induced lung injury.

The effects of exogenous MSCs are exerted through their isolation and injection into test animals. There are also some stem/progenitor cells that can be activated to proliferate when various tissues are injured. Basal cells (BCs), distributed throughout the pseudostratified epithelium from the trachea to the bronchioles, are a class of multipotent tissue-specific stem cells from various organs, including the skin, esophagus, and olfactory and airway epithelia [44, 45]. Previously, TPR63+/KRT5+ BCs were shown to self-renew and divide into club cells and ciliated cells to maintain the pseudostratified epithelium of proximal airways [46]. Several studies have shown that TPR63+/KRT5+ BCs play a key role in lung repair and regeneration after influenza virus infection. When animals typically recover from H1N1 influenza infection, TPR63+/KRT5+ BCs accumulate robustly in the lung parenchyma and initiate an injury repair process to maintain normal lung function by differentiating into mature epithelium [47]. Lineage-negative epithelial stem/progenitor (LNEP) cells, present in the normal distal lung, can activate a TPR63+/KRT5+ remodeling program through Notch signaling after H1N1 influenza infection [48]. Moreover, a population of SOX2+/SCGB1A/KRT5 progenitor cells can generate nascent KRT5+ cells as an early response to airway injury upon H1N1 influenza virus infection [49]. In addition, a rare p63+Krt5 progenitor cell population also responds to H1N1 virus-induced severe injury [50]. This evidence suggests that these endogenous lung stem/progenitor cells (LSCs) play a critical role in the repopulation of damaged lung tissue following severe influenza virus infection (Table2).

Taken together, the present in vitro (Table1) and in vivo (Table2) results show that MSCs and LSCs are potential cell sources to treat influenza virus-induced lung injury.

Lung injury caused by SARS, MERS, or SARS-CoV-2 poses major clinical management challenges because there is no specific treatment that has been proven to be effective for each infection. Currently, virus- and host-based therapies are the main methods of treatment for spreading CoV infections. Virus- and host-based therapies include monoclonal antibodies and antiviral drugs that target the key proteins and pathways that mediate viral entry and replication [51].The major challenges in the clinical development of novel drugs include a limited number of suitable animal models for SARS-CoV, MERS-CoV, and SARS-CoV-2 infections and the current absence of new SARS and MERS cases [51]. Although the number of cases of SARS-CoV-2-induced pneumonia patients is continuously increasing, antibiotic and antiviral drugs are the primary methods to treat SARS-CoV-2-infected patients. Similar to that of IAV, human CoV-mediated damage to the respiratory epithelium results from both intrinsic viral pathogenicity and a robust host immune response. The excessive immune response contributes to viral clearance and can also worsen the severity of lung injury, including the demise of lung cells [52]. However, the present treatment approaches have a limited effect on lung inflammation and regeneration.

Stem cell therapy for influenza virus-induced lung injury shows promise in preclinical models. Although it is difficult to establish preclinical models of CoV-induced lung injury, we consider stem cell therapies to be effective approaches to improve human CoV-induced lung injury. Acute inflammatory responses are one of the major underlying mechanisms for virus-induced lung injury. Innate immune cells, including neutrophils and inflammatory monocytes-macrophages (IMMs), are major innate leukocyte subsets that protect against viral lung infections [53]. Both neutrophils and IMMs are rapidly recruited to the site of infection and play crucial roles in the host defense against viruses. Neutrophils and IMMs can activate Toll-like receptors (TLRs) and produce interferons (IFNs) and other cytokines/chemokines [54]. There are two functional effects produced by the recruitment of neutrophils and IMMs: the orchestration of effective adaptive T cell responses and the secretion of inflammatory cytokines/chemokines [55]. However, excessive inflammatory cytokine and chemokine secretion impairs antiviral T cell responses, leading to ineffective viral clearance and reduced survival [56].

MSCs are known to suppress both innate and adaptive immune responses. MSCs have been suggested to inhibit many kinds of immune cells, including T cells, B cells, dendritic cells (DCs), and natural killer (NK) cells in vitro and in vivo [57] (Fig.1). Several molecules, including IL-1, TNF-, and INF-, most of which are produced by inflammatory cells, are reported to be involved in MSC-mediated immunosuppression [58]. Furthermore, MSCs can produce numerous immunosuppressive molecules, such as IL-6, PGE2, IDO, and IL-10, in response to inflammatory stimuli. PGE2 has been reported to mediate the MSC-mediated suppression of T cells, NK cells, and macrophages. Moreover, PGE2 has been found to act with IDO to alter the proliferation of T cells and NK cells [59]. In contrast, MSCs have come to be recognized as one type of adult stem cell actively participating in tissue repair by closely interacting with inflammatory cells and various other cell types [60]. Numerous reports have demonstrated that MSCs can release an array of growth and inhibitory factors, such as EGF, FGF, PDGF, and VEGF, and express several leukocyte chemokines, such as CXCL9, CCL2, CXCL10, and CXCL11. These factors provide an important microenvironment to activate adaptive immunity for lung repair [61]. Thus, the dual functions of MSCs may improve lung recovery after human CoV-induced ALI. Recently, MSCs was transplanted intravenously to enrolled patients with COVID-19 pneumonia. After treatment, the pulmonary function and symptoms of these patients were significantly improved. Meanwhile, the peripheral lymphocytes were increased, the C-reactive protein decreased, the level of TNF- was significantly decreased, and the overactivated cytokine-secreting immune cells disappeared. In addition, a group of regulatory DC cell population dramatically increased. Thus, the intravenous transplantation of MSCs was effective for treatment in patients with COVID-19 pneumonia [62, 63].

Stem cell therapies for treatment of influenza virus and coronavirus-induced lung injury. CoVs, coronavirus; MSCs, mesenchymal stem/stromal cells; LSCs, lung stem/progenitor cells; NK cells, natural killer cells; DC cells, dendritic cells

In addition, endogenous LSCs also play an important role in lung cell reconstitution after virus-induced ALI. In particular, TPR63+/KRT5+ airway BCs comprise approximately equal numbers of stem cells and committed precursors and give rise to differentiated luminal cells during steady state and epithelial repair after lung injury [44, 64]. Research has shown that KRT5+ cells repopulate damaged alveolar parenchyma following influenza virus infection [47]. However, there is still little evidence for the role of altered TPR63+/KRT5+ stem cells during lung injury repair caused by human CoVs.

In summary, exogenous MSCs may modulate human CoV-induced lung injury repair and regeneration through their immunoregulatory properties. These cells are capable of interacting with various types of immune cell, including neutrophils, macrophages, T cells, B cells, NK cells, and DCs. Furthermore, viral infections can activate endogenous LSCs to produce new lung cells and maintain lung function (Fig.1). Thus, we propose that MSCs and LSCs are two potential cell sources for treating human CoV-induced lung injury.

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Stem Cell Source Market Latest Research Report 2020:

The Stem Cell Source report provides an independent information about the Stem Cell Source industry supported by extensive research on factors such as industry segments size & trends, inhibitors, dynamics, drivers, opportunities & challenges, environment & policy, cost overview, porters five force analysis, and key companies

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In this report, our team offers a thorough investigation of Stem Cell Source Market, SWOT examination of the most prominent players right now. Alongside an industrial chain, market measurements regarding revenue, sales, value, capacity, regional market examination, section insightful information, and market forecast are offered in the full investigation, and so forth.

Scope of Stem Cell Source Market:Products in the Stem Cell Source classification furnish clients with assets to get ready for tests, tests, and evaluations.

Major Company Profiles Covered in This Report

BD Bioscience, Beckman Coulter, Ge Healthcare, Merck Millipore, Miltenyi Biotec, Pluriselect Life Science, Sigma-Aldrich Corporation, Stemcell Technologies, Terumo BCT, Thermo Fisher ScientificCompany 13,

1. To provide a detailed investigation of the market structure alongside conjecture of the different sections and sub-portions of the worldwide Stem Cell Source Market.

Stem Cell Source Market Report Covers the Following Segments:

Market segment by Type, the product can be split into

Reagent, Instrument, Others,

Market segment by Application, split into

Hospital, Biotechnology Research Center, Others,

Market segment by Regions/Countries, this report covers

United States

Europe

China

Japan

Southeast Asia

India

Central & South America

North America

Europe

Asia-Pacific

South America

Center East and Africa

United States, Canada and Mexico

Germany, France, UK, Russia and Italy

China, Japan, Korea, India and Southeast Asia

Brazil, Argentina, Colombia

Saudi Arabia, UAE, Egypt, Nigeria and South Africa

Table of Content:

Market Overview:The report begins with this section where product overview and highlights of product and application segments of the global Stem Cell Source Market are provided. Highlights of the segmentation study include price, revenue, sales, sales growth rate, and market share by product.

Competition by Company:Here, the competition in the Worldwide Stem Cell Source Market is analyzed, By price, revenue, sales, and market share by company, market rate, competitive situations Landscape, and latest trends, merger, expansion, acquisition, and market shares of top companies.

Company Profiles and Sales Data:As the name suggests, this section gives the sales data of key players of the global Stem Cell Source Market as well as some useful information on their business. It talks about the gross margin, price, revenue, products, and their specifications, type, applications, competitors, manufacturing base, and the main business of key players operating in the global Stem Cell Source Market.

Market Status and Outlook by Region:In this section, the report discusses about gross margin, sales, revenue, production, market share, CAGR, and market size by region. Here, the global Stem Cell Source Market is deeply analyzed on the basis of regions and countries such as North America, Europe, China, India, Japan, and the MEA.

Application or End User:This section of the research study shows how different end-user/application segments contribute to the global Stem Cell Source Market.

Market Forecast:Here, the report offers a complete forecast of the global Stem Cell Source Market by product, application, and region. It also offers global sales and revenue forecast for all years of the forecast period.

Research Findings and Conclusion:This is one of the last sections of the report where the findings of the analysts and the conclusion of the research study are provided.

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