Researchers from the University of Cambridge have harnessed mouse stem cells to create model synthetic embryos that comprise a brain, a beating heart, and the foundations of all the other organs of the body.

The team, led by Magdalena Zernicka-Goetz, PhD, mimicked natural processes, in the lab,without the use of eggs or sperm, by guiding the three types of stem cells found in early mammalian development to the point where they start interacting. By inducing the expression of a particular set of genes and establishing a unique environment for their interactions, the researchers were able to get the stem cells to talk to each other.

The stem cells self-organized into structures that progressed through the successive developmental stages until they had beating hearts and the foundations of the brain, as well as the yolk sac where the embryo develops and gets nutrients in its first weeks. Unlike other synthetic embryos, the Cambridge-developed mouse embryo models reached the point where the entire brain, including the anterior portion, began to develop. This is a further point in development than has been achieved in any other stem cell-derived model.

Our mouse embryo model not only develops a brain, but also a beating heart, all the components that go on to make up the body, said Zernicka-Goetz, who is a professor in mammalian development and stem cell biology in Cambridges department of physiology, development, and neuroscience.

The scientists say their results, which culminate from more than a decade of research that has progressively led to more and more complex embryo-like structures, could help scientists understand why some embryos fail while others go on to develop into a healthy pregnancy. Additionally, the results could be used to guide the development of synthetic human organs for transplantation. Its just unbelievable that weve got this far, Zernicka-Goetz continued. This has been the dream of our community for years, and the major focus of our work for a decade and finally weve done it.

Zernicka-Goetz, together with first author Gianluca Amadei, PhD, described their work in Nature, in a paper titled, Synthetic embryos complete gastrulation to neurulation and organogenesis, in which they concluded, these complete embryoids are a powerful in vitro model for dissecting the roles of diverse lineages and genes in development Because ETiX-embryoids capture extensive aspects of development, they provide a significant opportunity to uncover mechanisms of development and disease.

For a human embryo to develop successfully there needs to be dialogue between the tissues that will become the embryo, and the tissues that will connect the embryo to the mother. In the first week after fertilization, three types of stem cells develop: one will eventually become the tissues of the body, and the other two support the embryos development. One of these extraembryonic stem cell types will become the placenta, which connects the fetus to the mother and provides oxygen and nutrients; and the second is the yolk sac, where the embryo grows and where it gets its nutrients from in early development.

In natural development, the zygote develops into the epiblast, which will form the organism; the extraembryonic visceral endoderm (VE), which contributes to the yolk sac; and the extraembryonic ectoderm (ExE), which contributes to the placenta, the authors explained. Stem cells corresponding to these three lineages offer the possibility to completely regenerate the mammalian organism from multiple components, instead of from a single totipotent zygote. In vitro embryonic stem cells can undergo many aspects of mammalian embryogenesis, the team continued, but their developmental potential is substantially extended by interactions with extraembryonic stem cells, including trophoblast stem cells (TSCs), extraembryonic endoderm stem cells (XEN), and inducible-XEN cells (iXEN).

Many pregnancies fail at the point when the three types of stem cells begin to send mechanical and chemical signals to each other, which tell the embryo how to develop properly. So many pregnancies fail around this time, before most women realize they are pregnant, said Zernicka-Goetz, who is also a professor of biology and biological engineering at Caltech. This period is the foundation for everything else that follows in pregnancy. If it goes wrong, the pregnancy will fail.

Over the past decade, Zernicka-Goetzs group ihas been studying these earliest stages of pregnancy, in order to understand why some pregnancies fail and some succeed. The stem cell embryo model is important because it gives us accessibility to the developing structure at a stage that is normally hidden from us due to the implantation of the tiny embryo into the mothers womb, said Zernicka-Goetz. This accessibility allows us to manipulate genes to understand their developmental roles in a model experimental system.

To guide the development of their synthetic embryo, the researchers put together cultured stem cells representing each of the three types of tissue in the right proportions and environment to promote their growth and communication with each other, eventually self-assembling into an embryo. They discovered that the extraembryonic cells signal to embryonic cells by chemical signals but also mechanistically, guiding the embryos development. This period of human life is so mysterious, so to be able to see how it happens in a dishto have access to these individual stem cells, to understand why so many pregnancies fail, and how we might be able to prevent that from happeningis quite special, said Zernicka-Goetz. We looked at the dialogue that has to happen between the different types of stem cell at that timeweve shown how it occurs and how it can go wrong.

A major advance in the reported study is the ability to generate the entire brain, in particular the anterior part, which has been a major goal in the development of synthetic embryos. Our embryo model displays head-folds with defined forebrain and midbrain regions the investigators noted. The teams previous studies had used the same component cells to develop into embryos at a slightly earlier stage. Now, by pushing development just one day further, they say that their model is the very first to signal development of the anterior, and in fact the whole, brain.

This opens new possibilities to study the mechanisms of neurodevelopment in an experimental model, said Zernicka-Goetz. In fact, we demonstrate the proof of this principle in the paper by knocking out a gene already known to be essential for formation of the neural tube, precursor of the nervous system, and for brain and eye development. In the absence of this gene, the synthetic embryos show exactly the known defects in brain development as in an animal carrying this mutation. This means we can begin to apply this kind of approach to the many genes with unknown function in brain development.

As the authors noted, Importantly, we were able to replicate the consequences of Pax6 knockout in neurulating embryoids, which illustrates the potential of this complete embryo model to dissect the genetic factors that regulate development without the need of experimental animals.

In conclusion, they stated, Here, we show that we can assemble mouse embryonic and extraembryonic stem cells to form an embryo model that develops the brain, neural tube, heart, foregut, somite, allantois, primordial germ cells, and yolk sac structures. This embryo model is able to achieve this entirely through self-organization of these three stem cell types, without the need to provide any additional external signalling cues.

While the current research was carried out in mouse models, the researchers are developing similar human models, potentially enabling the development specific organ types that could help scientists understand mechanisms behind processes that would be otherwise impossible to study in real embryos. At present, under UK law, human embryos can be studied in the laboratory only up to the fourteenth day of development.

If the methods developed by Zernicka-Goetzs team are shown to be successful with human stem cells, they could feasibly be used to guide development of synthetic organs as human transplants. There are so many people around the world who wait for years for organ transplants, said Zernicka-Goetz. What makes our work so exciting is that the knowledge coming out of it could be used to grow correct synthetic human organs to save lives that are currently lost. It should also be possible to affect and heal adult organs by using the knowledge we have on how they are made.

This is an incredible step forward and took 10 years of hard work of many of my team membersI never thought wed get to this place. You never think your dreams will come true, but they have.

The newly reported work comes weeks after the publication, in Cell, of a study by a team led by co-author Jacob Hanna, PhD, at the Weizmann Institute. James Briscoe, PhD, principal group leader, assistant research director, Francis Crick Institute, said, that similar to the research recently reported by Hanna and colleagues, the study by Zernicka-Goetz and colleagues represented valuable proof of concept demonstration that a synthetic mouse embryo-like structure can be assembled from stem cells. By combining these cells together, the study shows that it is possible to coax the development of something that resembles a mouse embryo at a stage when the main organs of the body are beginning to be established, including the nervous system, heart, and gut, Briscoe said.

However, Briscoe pointed out that that formation of the synthetic embryos was very inefficient, that even the successful synthetic embryos appeared not as well organized as natural embryos, and that they didnt develop beyond what would be day 8.5 of normal embryonic development, which is just under halfway through a normal mouse pregnancy.

This emphasizes how much we still have to learn about how embryos build themselves, he noted. The technique reported in this study is a promising approach to provide new insights into how mammalian embryos organize and construct organs. Nevertheless, the study has broad implications as, although the prospect of synthetic human embryos still requires further research (as human embryos are not identical to mouse embryos), now is a good time to engage in wider discussions about the legal and ethical implications of such research.

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Synthetic Mouse Embryo with Brain and Beating Heart Grown from Stem Cells - Genetic Engineering & Biotechnology News

Rise In Research And Development Projects In Various Regions Such As East Asia, South Asia Are Expected To Offer An Opportunity Of US $ 0.5 Bn In 2022-2026 Period.

Fact.MR A Market Research and Competitive Intelligence Provider: The global induced pluripotent stem cell (iPSC) market was valued at US $ 1.8 Bn in 2022, and is expected to witness a value of US $ 2.3 Bn by the end of 2026.

Moreover, historically, demand for induced pluripotent stem cells had witnessed a CAGR of 6.6%.

Rise in spending on research and development activities in various sectors such as healthcare industry is expected to drive the adoption of human Ips cell lines in various applications such as personalized medicine and precision.

Moreover, increasing scope of application of human iPSC cell lines in precision medicine and emphasis on therapeutic applications of stem cells are expected to be driving factors of iPSC market during the forecast period.

Surge in government spending and high awareness about stem cell research across various organizations are predicted to impact demand for induced pluripotent stem cells. Rising prevalence of chronic diseases and high adoption of stem cells in their treatment is expected to boost the market growth potential.

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Besides this, various cells such as neural stem cells, embryonic stem cells umbilical cord stem cells, etc. are anticipated to witness high demand in the U.S. due to surge in popularity of stem cell therapies.

Key Takeaways:

Growth Drivers:

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Rise In Number Of CROS In Various Regions Such As Europe Is Expected To Fuel The Growth Of Induced Pluripotent Stem Cell Market At An Impressive CAGR...

Introduction

Glaucoma is one of the optic neuropathy disorders characterized by the progressive degeneration of retinal ganglion cells (RGC), which eventually lead to cupping of the optic disc and decreased visual field.1 Glaucoma is also closely related to an increase in intraocular pressure caused by the damage of trabecular meshwork (TBM), which results in optic nerve damage, characterized by the loss of retinal ganglion cells.2,3 Globally, in 2020, more than 76 million people are suffering from glaucoma, and it is expected to increase to 111.8 million people by 2040.4,5 Glaucoma is also a severe and complex medical problem because it often causes blindness. According to the World Health Organization (WHO), the most common causes of blindness are cataracts (51%), followed by glaucoma (8%), and age-related macular degeneration (5%).6 This data shows that glaucoma is the worlds second most common cause of blindness after cataracts. Symptoms that are often asymptomatic at an early stage and the low public awareness have contributed to the disorders seriousness.

Handling and treating glaucoma cases is difficult, especially because no therapy can cure glaucoma. Current treatment, both medical and surgical, is focused solely on lowering intraocular pressure. Treatment of glaucoma cases should also be carried out for life to maintain normal intraocular pressure and prevent the progression of intraocular damage due to glaucoma.7 Based on these problems, innovation is needed to handle glaucoma effectively. Besides, solutions are also required to repair the damage to retinal ganglion cells in glaucoma. One of the therapies that researchers are trying to take advantage of is stem cell therapy, a technology where cells can develop into many specific cells desired.8 In cases of glaucoma or optic neuropathies, damaged RGCs can be replaced with new ones grown from stem cells.9 Another option for RGC regeneration is to use retinal stem cells to regenerate RGCs. Indeed, stem cell therapy relies on exogenous stem cell sources due to their limited availability. Currently, many stem cell therapies for eye diseases that are created and studied are limited to treating the damage of photoreceptors and retinal pigment epithelium. iPSC-derived RGCs can serve as an excellent model for formulating approaches to promote de novo-generated RGCs to connect with their targets. Therefore, researchers have been looking into the potential use of modified stem cell therapy to treat the intraocular injury in glaucoma cases.10

This review aims to synthesize and prove the efficacy and further modification of this method so that it can be eligible for treatment and can also give data collection for the scientific community. This systematic review is expected to provide detailed information regarding the possible applications of modified stem cell therapy in treating intraocular damage in glaucoma patients.

In the present literature review, literature regarding the potential utilization of stem cells as an advanced therapy for intraocular glaucomatous damage was searched. The stages of this literature review include five steps: i) identifying the research question, ii) identifying relevant studies, iii) study selection, iv) charting the data, and v) summarizing and reporting the results.

This literature review was conducted to answer the following research questions:

The literature search was carried out from January to February 2021. Keywords and synonyms used to conduct literature searches related to the research question are attached in Table 1. Boolean operators (OR, AND, NOT) combine keywords when searching for literature. The search was conducted on seven online databases, namely PubMed, ScienceDirect, ProQuest, EBSCOhost, SAGE, Clinicalkey, and Scopus.

Table 1 Keywords That Were Used in the Database Search

The inclusion criteria for the literature search consisted of journals published in English and journals published in the last ten years. The exclusion criteria for selected studies consisted of journals that were not fully accessible due to the limited facilities owned as supporting access. We thoroughly screened the titles and abstracts of the studies obtained to suit the purpose of this literature review. Abstracts that were not relevant to the research objectives were excluded. Then a full article screening was carried out from the selected abstracts to identify whether the full article was suitable for the research objectives and whether the full article could be used to answer research questions.

Information obtained from all selected study articles is then displayed in the charting table The information displayed includes the author, year of publication, study objectives, location, study design, inclusion and exclusion criteria, results, and conclusions.

The researcher did not assess the quality of the selected articles because this study was only a literature review. The data from selected studies are reported to produce recommendations for further research regarding the use of stem cell therapy in glaucoma cases.

Based on the literature search that has been conducted, a total of 2262 studies and abstracts were included in the journal screening process at an early stage. From this screening process, 362 duplicate articles were excluded from the selection. The remaining 1900 articles then entered the abstract eligibility screening stage. Only 53 articles were selected, while 1879 other articles were excluded. Of the 53 articles, 18 articles appeared relevant to the study and met the inclusion criteria for review throughout the study. Meanwhile, 35 other studies were excluded because the focus in these studies did not match the objectives of this literature review. After assessing the full articles, six studies met the inclusion criteria in this literature review (Figure 1).

Figure 1 Flow diagram of the literature review process.

In Table 2, a summary of the characteristics of the selected studies is presented. The data used from selected studies include research objectivity, study design, results, outputs, and conclusions from the study. Of all the selected studies, there were six studies that had experimental methods. Almost all studies have the aim of evaluating and proving the potential of using stem cells to replace damaged tissue and restore and restore the function of damaged eye tissue, particularly due to degenerative processes such as disease of the retina or glaucoma.

Table 2 Results Summary of the Characteristics of the Selected Studies

Glaucoma is characterized by the degeneration of retinal ganglion cells. Based on the pathophysiology, glaucoma can be divided into two categories, namely open-angle glaucoma and closed-angle glaucoma. In patients with open-angle glaucoma, there is increased resistance to the aqueous humors outflow through the trabecular meshwork. This increased resistance is often caused by apoptosis and senescence of trabecular meshwork cells with increasing age.15 Degradation and abnormalities of the cytoskeleton arrangement of trabecular meshwork cells resulting in thickening of the drainage pathways and abnormal extracellular matrix deposition also worsen trabecular meshwork function in open-angle glaucoma.16 In closed-angle glaucoma, the aqueous humor cannot reach the trabecular meshwork due to obstruction.17 Examples of obstructions that often cause closed-angle glaucoma are anterior synechiae, the attachment of the iris to the trabecular meshwork, and posterior synechiae, where the iris is attached to the lens. This adhesion causes the aqueous humor to fail to reach the drainage system and the trabecular meshwork.18

Glaucoma is closely related to increased intraocular pressure, which is determined by the balance between the production of aqueous humor by the ciliary body and the drainage of the aqueous humor through the trabecular meshwork. The disturbance of the balance between production and drainage increases the humor Aquos, which at a later stage can increase the intraocular pressure.19 Studies have shown a link between increased intraocular pressure and retinal ganglion cell death. This study has also proven that the longer the intraocular pressure increases, the higher the degree of retinal ganglion cell damage.20 However, data show as many as 3040% of patients with glaucoma have normal intraocular pressure. One of the causes of glaucoma at normal intraocular pressure is a decrease in neurotrophic factors needed in the maintenance of neurons in the optic nerve. Neurotrophic factors are required to maintain retinal ganglion cells, including brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), and cell line-derived neurotrophic factor.21 Furthermore, microcirculation disorders, changes in immune system conditions, and increased levels of oxidative stress can also cause glaucoma at normal intraocular pressure.21

Stem cells are cells with the ability to differentiate and form all tissues in the human body. They are one of the potential therapies used in cases that require tissue repair and regeneration, one of which is glaucoma. For a cell to be called a stem cell, it must have two essential characteristics. The first one is the stem cell must produce offspring with the exact features the cell originates from, and the second one, the stem cell must be able to differentiate into the specific cell desired.22 There are two types of stem cells found in multicellular organisms, including humans. The first stem cells are embryonic stem cells or multipotent cells found in blastocysts, while the second stem cells are adult stem cells or pluripotent cells that can be found in a wide variety of adult tissues.23

Research has also succeeded in inducing adult cells to return to the pluripotent stage using molecular manipulation. The cells produced by this molecular manipulation are then called induced pluripotent stem cells (iPS).24 Most iPS manufacturing uses viruses such as retroviruses and lentiviruses to carry genes encoding transcription factors to adult cells to be modified. This gene will then undergo transcription and translation into a protein capable of inducing the adult cell nucleus to return to an embryonic state.25

An important concept that needs attention in stem cell therapy is how to induce stem cells to become the desired differentiated cells.26 It is necessary so that the cells can be used to treat various diseases, including glaucoma. We can further achieve differentiation of stem cells into specific desired cells by adding various growth factors and signaling pathways to resemble the conditions of their original development.27

The research conducted successfully isolates cultures and confirms that the trabecular meshwork stem cells around the Schwalbe line are multipotent with the ability to differentiate into a wide variety of cells, including trabecular meshwork cells adipocytes osteocytes, and chondrocytes.28 Other studies have also been able to induce stem cells on the Schwalbe line trabecular meshwork to proliferate and differentiate into photoreceptors under certain conditions.29 Apart from trabecular meshwork stem cells, other stem cells that can differentiate into functional meshwork trabecular cells are adipose-derived stem cells (ADSC), mesenchymal stem cells (MSC), and iPS. iPS cells can also differentiate into trabecular meshwork cells after culturing the extracellular matrix with cell-derived trabecular meshwork. The success of a wide variety of stem cells to differentiate into functional meshwork trabecular cells provides a more effective alternative to cutting-edge therapy in treating glaucoma, especially open-angle glaucoma.3

One of the stem cell therapies successfully applied and able to regenerate damaged retinal ganglion cells is iPS cell therapy. This therapy uses induced adult fibroblasts to return to pluripotent cells using four transcription factors, namely Oct3/4, Sox2, Klf4, and c-Myc. The results of the iPS are pluripotent cell colonies that are morphologically similar to ESCs, which are able to differentiate into the three germ cell layers.30

Because iPS can be programmed from the patients somatic cells, this therapy can maintain the unique genome of each individual. Currently, various modifications to the iPS therapy have been made to increase its acceptability and effectiveness of iPS therapy. One of them is the use of plasmid vectors and miRNA instead of retroviruses to avoid mutagenesis of the adult cells used.31,32

One of the significant challenges in stem cell therapy is to achieve the differentiation of stem cells into the desired cells, in this case, the differentiation of stem cells to retinal ganglion cells. Usually, in vivo, the differentiation of stem cells into retinal ganglion cells is regulated by several transcription factors such as Ath5, Brn3, and Notch. The transcription factors Ath5 and Brn3 play a vital role in the differentiation of retinal ganglion cells, and their levels are increased in the process of eye development.33 Meanwhile, Notch is a negative regulator of retinal ganglion cell differentiation, and its levels are decreased in normal eye development. Therefore, the addition of the transcription factors Ath5 and Brn3 and the Notch antagonist is a strategy to differentiate retinal ganglion cells from stem cells.34 Apart from transcription factors, various neurotrophic pathways and factors have been identified in the differentiation of stem cells into retinal ganglion cells. These pathways consist of fibroblast growth factor (FGF), insulin-like growth factor (IGF), bone morphogenetic protein (BMP), nodal, and Wnt signaling pathways. All of these pathways regulate retinal development, whereas FGF and IGF provide positive regulation. Meanwhile, BMP, nodal, and Wnt signaling pathways provide negative regulation.35

Another major challenge in the clinical application of stem cell therapy in glaucoma sufferers is that not only do the stem cells successfully differentiate into retinal ganglion cells, but they must also be able to reach the central nervous system.36 Modifications must be made so that new retinal ganglion cells can reach the visual cortex of the cerebrum. Recent research has found that a combination of genetic modification and stimulation of the signaling pathway stimulates regeneration of the optic nerve until it reaches the central nervous system. The addition of ephrin molecules, proteoglycans, cell-adhesion molecules, and semaphorin is able to guide the axons of the developing retinal ganglion cells to reach the optic chiasm.13 Meanwhile, the addition of cadherin, ephrin, and the Wnt signaling pathway can guide and stimulate synapse formation in the superior colliculus and the visual cortex.12,37

In addition, because of the adverse intraocular environment in glaucoma, stem cell therapy needs to be combined with neuroprotective compounds. It is also associated with a decrease in neurotrophic factors required to maintain neurons and causes progression of retinal ganglion cell damage in glaucoma sufferers. Therefore, the addition of BDNF and other neurotrophic factors such as glial cell-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) should be considered for combined stem cell therapy.38

The stem cells are used in cases of glaucoma, which require repair and regeneration of trabecular meshwork cells and retinal ganglion cells. iPS has been shown the ability to differentiate to replace damaged trabecular meshwork cells and retinal ganglion cells in glaucoma. Some modifications are required so that stem cells that have differentiated into trabecular meshwork cells and retinal ganglion cells can reach the central nervous system. These modifications include the addition of ephrin molecules, proteoglycans, cell-adhesion molecules, semaphorin, cadherin, and the Wnt signaling pathway. The combination of stem cells with neuroprotective factors such as BDNF, GDNF, and CNTF also needs to be considered to maintain neuronal maintenance and inhibit the progression of cell damage.

The development of new stem cell technologies not only paves the way for us to gain a better understanding of the biology associated with glaucoma and create models for the development of new drugs, but it also opens the door to the prospect of cell-based therapies that can help patients regain their vision. More specifically in relation to the field of glaucoma, there have been recent developments in the process of developing protocols for the differentiation of stem cells into trabecular meshwork and retinal ganglion cells. Further research on the effectiveness of using modified stem cells as a therapy for glaucoma and in vivo research can be carried out immediately so that clinical trials can be carried out, which in turn can be used by the community to control symptoms and reduce blindness due to glaucoma.

The authors report no conflicts of interest in this work.

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24. Zaveri L, Dhawan J. Cycling to meet fate: connecting pluripotency to the cell cycle. Front Cell Dev Biol. 2018;6. doi:10.3389/fcell.2018.00057

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26. Kolios G, Moodley Y. Introduction to stem cells and regenerative medicine. Respiration. 2012;85(1):310. doi:10.1159/000345615

27. Biehl JK, Russell B. Introduction to stem cell therapy. J Cardiovasc Nurs. 2009;24(2):98103; quiz 1045. doi:10.1097/JCN.0b013e318197a6a5

28. Tay CY, Sathiyanathan P, Chu SWL, Stanton LW, Wong TT. Identification and characterization of mesenchymal stem cells derived from the trabecular meshwork of the human eye. Stem Cells Dev. 2012;21(9):13811390. doi:10.1089/scd.2011.0655

29. Nadri S, Yazdani S, Arefian E, et al. Mesenchymal stem cells from trabecular meshwork become photoreceptor-like cells on amniotic membrane. Neurosci Lett. 2013;541:4348. doi:10.1016/j.neulet.2012.12.055

30. Omole AE, Fakoya AOJ. Ten years of progress and promise of induced pluripotent stem cells: historical origins, characteristics, mechanisms, limitations, and potential applications. PeerJ. 2018;2018. doi:10.7717/peerj.4370

31. Miyoshi N, Ishii H, Nagano H, et al. Reprogramming of mouse and human cells to pluripotency using mature microRNAs. Cell Stem Cell. 2011;8(6):633638. doi:10.1016/j.stem.2011.05.001

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Utilization of Modified Induced Pluripotent Stem Cells as the Advance | OPTH - Dove Medical Press

What Are Hematopoietic Stem Cells and Why Are They Important? Hematopietic stem cells (HSCs) are multipotent cells found in the blood and bone marrow with the ability to self-renew and differentiate into multiple cell types during bone marrow hematopoiesis. Clinicians use HSCs to replace or repopulate a patients blood as a form of regenerative medicine. Research into HSC development and aging facilitates better in vitro HSC expansion and broadens their potential for disease treatment, enhancing their clinical therapeutic effects.

How Hematopoietic Stem Cells DevelopHSCs begin their development during embryogenesis in the dorsal aortic tissue and are additionally found in the placenta, yolk sac, and fetal liver. This fetal hematopoiesis process is necessary to produce the blood cells required for tissue development while generating a pool of undifferentiated HSCs. At birth, these HSCs migrate into and populate the newly-formed bone marrow and maintain a steady state of self-renewal and differentiation.1 HSCs function by producing red blood cells, platelets, and white blood cells throughout life, maintaining their levels following bleeding and infection. HSCs generally give rise to partly differentiated but proliferative progenitors, which differentiate into mature cells. Because of this process, true HSCs are relatively rare in the human body.2

Using Hematopoietic Stem Cells for Research and TreatmentHematopoietic stem cell transplantsFor more than 60 years, hematopoietic stem cell transplants (HSCTs) have been the most common form of HSC therapy, and are a standard option for treating hematologic malignancies, immunodeficiency, and defective hematopoiesis disorders. HSCs are now derived from multiple sources, such as peripheral and cord blood and bone marrow. Before transplantation, the receiving patient must undergo severe immunosuppressive procedures to prevent rejection of the new stem cells.3

Hematopoietic stem cell isolationThe most common HSC isolation method involves removing blood cells from plasma using density gradient centrifugation followed by magnetic bead isolation using the CD34+ surface marker, a general marker for all hematopoietic progenitors. Using flow cytometry, scientists sort specific HSC cell types based on common cell surface markers.4 Clinicians then intravenously infuse these cells into the receiver patients marrow where they engraft and repopulate the blood and immune system. In blood cancers such as leukemias and lymphomas, restoration of the blood system by HSCT allows patients to receive high-dose chemotherapy treatments, ridding them of malignant cells. In patients with red blood cell conditions where continuous blood transfusions are not an option, such as thalassemia major, HSCT results in 80 percent disease-free survival.5

Hematopoietic stem cells in gene and tissue regeneration therapyBone marrow hematopoietic stem cells also differentiate into cells of other lineages, such as endothelial cells, cardiomyocytes, neural cells, and hepatocytes, in a process called transdifferentiation. Because adult stem cells are rare, understanding the mechanisms behind HSC transdifferentiation could provide an additional source of tissue-specific multipotent cells and influence future clinical methods for tissue regeneration. HSCs can also help repair injured organs by releasing regenerative cytokines and recruiting cells to the damage site.5 Some of the latest advances in HSC therapeutic research involve using methods such as CRISPR for correcting genetically-defective HSCs. These methods will allow a patient to receive their own genetically-compatible (syngeneic) HSCs. These are called allogeneic transplants and are more effective at avoiding graft-versus-host disease, a condition where transplants from a donor are rejected by the recipients body, leading to an immune response against other tissues and organs. Creating genetically-corrected induced pluripotent stem cells (iPSCs) from patient skin tissues and differentiating them into HSCs has also been an active area of research, although current methods remain costly and time-consuming.6 Further research is necessary to take advantage of these remarkable multipotent cells in disease therapies.

References

1. H.K. Mikkola, S.H. Orkin, The journey of developing hematopoietic stem cells, Development, 133(19):3733-44, 2006.

2. G.M. Crane et al., Adult haematopoietic stem cell niches, Nat Rev Immunol, 17(9):573-90, 2017.

3. S. Giralt, M.R. Bishop, Principles and overview of allogeneic hematopoietic stem cell transplantation, Cancer Treat Res, 144:1-21, 2009.

4. B. Kumar, S.S. Madabushi, Identification and isolation of mice and human hematopoietic stem cells, Methods Mol Biol, 1842:55-68, 2018.

5. J.Y. Lee, S.H. Hong, Hematopoietic stem cells and their roles in tissue regeneration, Int J Stem Cells, 13(1):1-12, 2020.

6. S. Demirci et al., Hematopoietic stem cells from pluripotent stem cells: Clinical potential, challenges, and future perspectives, Stem Cells Transl Med, 9(12):1549-57, 2020.

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Brush Up: Hematopoietic Stem Cells and Their Role in Development and Disease Therapy - The Scientist

Researchers from the Murdochs Children Research Institute (MCRI) are developing new treatments for congenital heart disease that could enable children born with birth defects can regenerate the damaged organ.

In 2011, Prof. Enzo Porello, who is nowhead of the Heart Regeneration Laboratory at the MCRI,demonstrated the regenerative properties of newborn mouse hearts at the University of Texas Southwestern Medical Centre. Prior to this research, the capacity of mammalian hearts to regenerate was a debated topic.

This sort of changed our thinking of what was possible in terms of stimulating the human heart to regenerate itself following damage, such as a heart attack, Porrello said, reported theAustralian. And I guess this also fuelled my own interest in my subsequent career in the area of regenerative medicine.

After hearing about cases where newborns recovered from massive heart attacks, Porello began to explore the regenerative properties of human newborn hearts.

In 2017, Porello and Prof. James Hudson manufactured living and beating heart tissues from stem cells in a laboratory at the University of Queensland.

Porello said that although other scientists had grown heart muscle cells from stem cells, nobody had grown the cells as miniature complex three-dimensional tissues. Additionally, they were not able to grow such tissues in a format compliant to drug development, he said.

And thats really the technological breakthrough that we were able to make.

According to the Australian Institute of Health and Welfare, approximately 9 out of every 1,000 babies born around the world will be born with congenital heart disease. In Australia, it is estimated that 2,400 babies are born with congenital heart disease annually, while in America, nearly one percent of all babies born are estimatedby the Centre For Disease Control to have the condition.

Porello said that, at the moment, if a child develops heart failure and doesnt respond to standard frontline therapies, a heart transplant is their only option. Children in this situation are put on a transplant waiting list, and whilst waiting for a heart to become available, they are put on mechanical support.

Heart transplantation is limited by organ donor availability, and its also limited by the need for lifelong immunosuppression in those patients, Porello said.

And so if were able to develop these bioengineered heart tissues from stem cells, this could potentially prevent or delay the need for heart transplantation in these very unwell individuals with end-stage heart failure.

Porello said that the ultimate goal of his research is to harness the self-repairing capacity of the newborn heart and to develop drugs that waken the hearts dormant regenerative abilities so that the organ may repair itself after damage.

I would say that based on recent studies in the field in the past 10 years since we first made our discovery in mice, we are certainly getting closer, he said.

There is sort of proof of concept that this is possible now, at least in mice, and the question is whether or not we can now make that a therapeutic reality in humans.

The first step in creating these complex heart tissues is attaching special molecules to stem cells; these molecules trigger the cells to morph into heart muscle tissue. The heart tissues are then developed in a plastic culture dish that consists of 96 tiny wells.

The geometry of the well is designed in such a way that the heart tissues spontaneously form when the heart muscle cells are inserted into the well, Porrello said.

He said that within each well of the device are tiny elastic micropillars; the pillars function as elastic cantilevers since they are attached to the dish at only one end and extend horizontally to the dish. The heart muscle cells condense around these cantilevers to produce tiny miniature beating heart tissues that contract around the micropillar; every time the tissue contracts, the micropillar within it deflects.

Porello said that the device enables researchers to measure the force that the tissues are generating, allowing them to observe how fast the tissues are beating and whether they display any irregularities in their heartbeat. These capabilities are useful for treatment testing because the effect that medication or genetic manipulations of stem cells have on the tissues heartbeat can be seen.

And so it serves as a pretty powerful platform for looking at drug responses, but also modelling genetic forms of heart disease.

Were actually now scaling up these tissues and growing very, very large bioengineered heart tissue patches that can be implanted onto the heart.

In an email to The Epoch Times, Porello said in the future that bioengineered heart tissue patches could be used to treat adults with heart failure, and alternative approaches are already being trialled.

Our bioengineered heart tissues could also be used to support the failing heart in adults with underlying heart disease.

Further studies are required to confirm that our bioengineered heart tissue patches are safe and effective in animal models before progressing to human trials. These pre-clinical safety and efficacy studies are underway.

He noted that although significant advances and a better understanding of the hearts regenerative mechanisms have been made in recent years, using this knowledge to develop a safe and effective drug is a slow process.

It typically takes 10 years and around $1 billion dollars to develop a new heart failure drug and take it all the way through to clinical approval. We are at the beginning of that journey.

We need to gain a better understanding of the fundamental biology underlying heart regeneration before we can develop effective treatments.

Porello is now applying his discoveries in a clinical context at theMCRIto reach his goal of regenerating human hearts. The regeneration research at the institute has two branches, the first focuses on studying diseases using lab-grown models of the heart muscle. The models are made using blood and tissue samples collected from sick children at the Royal Childrens Hospital in Melbourne.

He said that this branch of the research enables the team to model the genetic basis of the disease in any individual.

Were using this technology to model childhood heart disease, trying to understand its causes, and then using those genetic models of heart disease to test and develop therapeutic approaches to treat those conditions, he said.

Porello said that the second branch of the research performed at the MCRI explores the regenerative approach to growing the very, very large bioengineered heart tissue patches. The researchers plan is to eventuallyimplant the patches into a heart to function as a biological assistance device that supports the function of the heart.

If it works, it would be transformative, Porello said.

Stem cells have been used in medicine for more than fifty years, with the most common stem cell procedure currently beingbone marrow transplantsalso known as hematopoietic stem cell transplantsused to treat patients with blood cancers such asleukemiaand blood disorders such assickle cell diseaseandthalassemia.

More recently, skin grown from stem cells has been used to treat extensive burns, and stem cells from fat (adipose tissue) have been used as tissue fillers.

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Regenerative Properties of the Newborn Heart Offers Hope for Those With Congenital Heart Disease - The Epoch Times