Category Archives: California Stem Cells

Sustenance of visual function is the ultimate focus of ophthalmologists. Failure of complete recovery of visual function and complications that follow conventional treatments have shifted search to a new form of therapy using stem cells. Stem cell progenitors play a major role in replenishing degenerated cells despite being present in low quantity and quiescence in our body. Unlike other tissues and cells, regeneration of new optic cells responsible for visual function is rarely observed. Understanding the transcription factors and genes responsible for optic cells development will assist scientists in formulating a strategy to activate and direct stem cells renewal and differentiation. We review the processes of human eye development and address the strategies that have been exploited in an effort to regain visual function in the preclinical and clinical state. The update of clinical findings of patients receiving stem cell treatment is also presented.

Blindness or loss of visual function can be caused by failure of the light path to reach the retina or failure of the retina to capture and convert light to an electrochemical signal before transmission to the brain via optic nerve [1]. The major causes contributing to blindness include age-related macular degeneration (ARMD), diabetic retinopathy, cataracts, and glaucoma [24], which are genetically linked [5] and associated with multiple risk factors including diet [6], hypertension [7], pregnancy [8], and smoking [9]. The occurrences of these pathologies increase with the age of the patient and are thus widely spread among aging populations. Blindness is an extensive disease that not only affects the quality of life of the patients themselves but may have a negative impact on the socioeconomic status of their immediate families [10, 11].

Current treatments have aimed at protecting vision and preventing visual impairment by early diagnosis using various methods of intervention such as surgery, ionizing radiation, laser, or drug treatments [1214]. Despite the efficiencies of these treatment modalities, they do not provide a complete solution to stop the progression to blindness.

Many recent findings from preclinical data have supported the notion that stem cells have the capacity to revive degenerated cells or replace cells in many major diseases including ocular disorders [1518]. Stem cells are present in all tissues in our body and are self-renewable and capable of maintaining a certain level of differentiation in response to injury for tissue repair [1921]. We mainly aimed this review at both clinicians and academicians, so we presented the localization of stem cell progenitors with eye development in different regions in the eye, the functions of these progenitors, and the current clinical trials and their exploitation of nontissue specific stem cells as alternative sources for regaining lost vision.

Eye development involves indispensable participation of the neural ectoderm (NE), surface ectoderm (SE), ectomesenchymal/cranial neural crest cell (CNCC), and modicum of mesenchymal tissues [22]. During the fourth week of intrauterine life, the forebrain gives rise to two bulges called optic vesicles that extend like a stalk and a cup to trigger the surface ectoderm on both sides [22]. The retinal pigmented epithelium (RPE) and neural retina (NR) are developed from outer and inner layer of optic cup, while the optic nerve is developed from optic stalk [22]. The cup tip becomes the ciliary body and iris by integrating with the CNCC [23]. The surface ectoderm is repressible for the lens, cornea, and conjunctiva [24]. The sclera, corneal endothelium, corneal stroma, iridial stroma, and iridial muscles are contributed by the CNCC [25]. The neural ectodermal derivatives of eye are permanent cells and lack the self-renewal, as like other nervous tissues. But unlike other surface ectodermal derivatives, the ocular ectodermal derivatives do lack the self-renewal in the eye during aging which collectively results in various degenerative disorders.

The well-organized time-dependent interactions and gene expression of all these layers for initiation, pattern determination, and organogenesis are significant for eye development [22, 2427]. Eye development in an embryonic mouse at 9.5 days is shown in Figure 1 [26]. The neural ectoderm bulges as the optic vesicle to reach the surface ectoderm. The surface ectoderm becomes thicker on contact with the neural ectoderm to become the lens placode. Except in the lens placode region, the neural ectoderm and the surface ectoderm are separated by the extraocular mesenchyme. In the NE, the presumptive RPE, NR, and optic tract are colored red, green, and yellow, respectively, in Figure 1. The lens placode is colored blue in Figure 1. The transcription factors described in Figure 1 are involved in the regulation of eye development.

Pax6 is a crucial and evolutionarily conserved homeobox gene of eye development [28, 29]. Along with Pax6, the other associated genes reported for eye development are Rx/Rax, Pax2, Lhx2, Mitf, Otx2, Sox2, Six3, Pitx, Vsx2, Crx, Optx2, and FaxL2 [2839]. The expression of Pax6 is upregulated by Six3 and downregulated by Shh (Sonic hedgehog) [35] to help eye formation on both sides [39]. The transcription factor Pax2 is important for the formation of the optic stalk (which becomes the optic nerve). Retinal axons from both the eyes selectively decussate at the midline named optic chiasma (crucial for vision) which is failed when the Pax2 mutates (optic chiasma) [23].

Initiation of optic vesicle formation from the neural ectoderm by Rx/Rax involves extensive cell movements and proliferation [36]. In addition, Rx is essential for expression of Lhx2, Pax6, Mab2112, and Six3, which specifies the retinal progenitor cells in the optic cup [30, 31, 36, 37]. Lhx2, a patterning gene expressed in the neural ectoderm, is important for expression of Mitf [32]. Mitf is a governing gene for RPE that specifies the neural retina, and in the neural ectoderm, RPE regulates the vesicle to cup transformation and activates the retinoid acid receptor, which is another important factor for eye development [33, 34]. In Lhx2 mutant mouse, Mitf and Vsx2 are never initiated and Pax2, Vax2, and Rx are initiated but not maintained, resulting in arrest of eye development in the optic vesicle stage [40]. The optic vesicle is important for lens formation and the lens is important for the vesicle to cup formation. The surface ectoderm will not form the lens if the optic vesicle is removed. In contrast, when provided with an optic vesicle, any primitive ectoderm will develop into the lens [40].

The neural retina, the brain of eye with nine distinct layers, transmits color signals in and out as vision [22]. During development, the neural retina depends on the expression of Vsx2, an important homeobox gene for early patterning and maintenance of cell proliferation and fate [41]. MAPK/FGF signaling is important for neural retina and upregulates Vsx2 [42] and Vsx2 downregulates Mitf [4244]. This regulation helps control the distinct neural retina and RPE specification in the optic cup. FGF9, normally expressed in the distal optic vesicle, is important for the boundary between the neural retina and the RPE [4446]. FGF receptor activation is crucial in chicks but not in mice [46]. This suggests that there is species-specific neurogenesis. Interestingly, specific activation of MAPK/FGF can induce neural retina formation from presumptive RPE with distinct layers [43, 45, 4749]. BMP is important for Vsx2 regulation [50]. Figure 2 shows a schematic of the adult eye of different vertebrates (frogs and fish, birds, and human) [27]. The ciliary marginal zone (CMZ, yellow color in Figure 2) is progressively reduced in higher vertebrates. Unlike the earlier vertebrates, the neural retina in mammals (blue color in Figure 2) is not renewed continuously because of the absence of the CMZ [51]. The neural progenitor marker Nestin is expressed in the junction of the ciliary body with the neural retina, suggesting the remaining of a CMZ even though the relationship is not clear [52]. The regeneration studies reported with RPE to neural retina are akin to transdifferentiation under suitable conditions [53].

Mller glial cells are a progenitor glial component of the neural retina, which arise from activation of Notch, Rax, and Jak signaling pathway [54]. The RPE is an array of uniformly arranged cells in a single layer between the retina and choroid [22]. MITF governs the RPE, the bHLH transcription factor that is the first and critical gene expressed in presumptive RPE and is specific for patterning and cell proliferation [38]. Mitf, the regulator of the pigmented cells (both in the RPE and in the CNCC) is expressed even before the pigments are formed in the RPE [24]. Mitf is initially expressed throughout the optic vesicle but is later downregulated in neural retina for layer specification. Otx2 is important for Mitf expression [33]. Pax regulates both the Mitf and Otx2 [55]. Pax2 and Pax6 bind and activate the Mitf A enhancer [35]. Retinoid acid signaling regulates the optic cup morphogenesis and induces apoptosis in extraocular mesenchyme [33]. Retinoid acid receptors (RAR-,,) are important for signal transduction of retinoic acid, which is important for the maintenance of the RPE [56]. The enzymes, retinaldehyde dehydrogenases (Raldh) 1, 2, and 3, are vital for retinoid acid synthesis. Raldh 3 originates from the RPE, and Raldh 2 originates from the surrounding mesenchyme [57]. Pitx2 is also important for RPE differentiation [58]. The fate of RPE is influenced by Shh [59]. Growth arrest specific 1 (Gas1) is a (GPI) protein that binds and coregulates with Shh [60]. Gas1 downregulates the proliferation of the RPE to maintain a single cell-layered structure [60]. There are reports of the distinct control mechanisms by BMP in the ventral and dorsal aspects of the RPE [61]. The Wnt/-catenin pathway also controls the optic cup differentiation by activating Mitf and Otx2 [62].

The ciliary body and the iris are developed from the optic cup tip with the incorporated connective tissue stroma derived from the migrated CNCC. The smooth muscles of the iris, namely, the sphincter and dilator pupillae, are derived by transdifferentiation of the pigmented epithelial cells of neural origin [43, 63]. The iris and ciliary body regulate the light reaching the retina and maintain the intraocular pressure by maintaining the aqueous humor secretion [61, 64]. The pigmented cells of the iris possess the ability to differentiate into RPE, neural retina, and lens, and a potential source of stem cells in mammals [65]. FGF, BMP, and Wnt/-catenin participate in the differentiation of progenitor cells into ciliary and iris epithelium [45, 66].

The lens is derived from the surface ectoderm upon receiving instruction by Pax6 to respond to FGF, BMP, and Sox2. Fox-3 helps in the separation of the lens from the surface ectoderm and formation of lens fibers. Lens fibers are epithelial cells that undergo clever modification to become transparent fibers by losing their organelles and accumulating crystalline protein; Pax6, Pitx3, c-Maf, HSF4, RAR, Six, Sox, and Prox are the transcription factors related to crystalline genes [66, 67]. The CNCC is crucial for eye development and restricts the lens formation area in the surface ectoderm by inhibiting cells other than those for the lens. The lens is under the control of the retina throughout life. The retinal secretion of FGF accumulates in the vitreous humor and stimulates the lens part facing the retina to form lens fibers. If the developing lens is rotated, the cell type changes to form lens fibers from the surface facing the retina (Figure 3) [23]. Attempt can be made to turn the defective lens, front to back to find the results, because the side of the lens which faces the retina is influenced with better survival.

The optic cup is surrounded by mesenchymal cells predominantly of CNCC origin that help in the formation of the vascular coat called the choroid and fibrous coat, namely, the sclera. Transcription factors involved with the scleral development are Foxc1, Foxc2, Lmx1b, Pax6, Pitx2, RARb, RARg, RXRa, Six3, and Smad2 [30, 31, 36, 39].

The corneal epithelium is continuous with the conjunctiva covering the visible part of the sclera. The junction between the corneal and conjunctiva is named the limbus, which holds stem cells for the renewal of the epithelium throughout life [22]. The corneal epithelium is constantly renewed every 7 to 10 days. Corneal epithelium expresses Np63, ABCG2, integrin 9, Bmi-1, EGFR, TGF, and PDGF growth factor indicators for their stemness. The stromal interaction is important for the cell renewal achieved by paracrine factors, hepatocyte growth factor (HGF), and keratinocyte growth factor (KGF). These factors are fibroblast-derived epithelial mitogens of the FGF7 family. In the corneal endothelium the morphology, collagen expression, and cell proliferation are maintained by TGF-1 and TGF-2 [46, 49]. Altogether, the corneal endothelial integrity is preserved by Pax6, Lmx1b, and Pitx2 [37].

The tissues of eye which are commonly associated with diseases are the surface ectoderm derivatives cornea and lens and the neural ectoderm derivatives RPE and retina. Since the lens and cornea do lack the renewal capacity during aging, stem cells from other surface ectoderm derivatives which are relatively easy to collect can be reprogrammed by manipulating target genes and proteins with the help of gained knowledge from molecular biology for regenerative therapy. Regenerated lenses from stem cells can be more exciting personalized regenerative treatment.

The aim of understanding the sequential events during embryogenesis at molecular level cell to cell communication is to understand the pathogenesis and to design the regenerative or genetic therapy to restore normal. The commonest degenerative eye disorders can be tactfully managed by delivering target proteins to prevent and to repair several types of ocular diseases. Stem cells of eye are closely associated with maxillofacial tissues including dental stem cells (a derivative of CNCC) during embryogenesis which retain the stem cells till life can be traced and reprogrammed for stem cell therapy. Researchers differentiated retina [68] from dental pulp stem cells. Epigenetic memory explains that the differentiated cells retain the memory of their original tissue and on reprograming they spontaneously dedifferentiate to its original tissue [69, 70]. If the suggested RPE differentiation from dental stem cells [71] is succeeded, it will be more acceptable than the controversial embryonic stem cells, which has proven its success after 2 years of follow-up of clinical trial [72, 73]. Autologous oral mucosal epithelial cells have been successfully reconstructed to fabricate cornea to restore vision [74].

To dispense a suitable intervention, the mechanism that regulates cell renewal, differentiation, and maturation change in a diseased microenvironment needs to be understood. One of the major inherited ocular disorders, Retinitis Pigmentosa (RP), is characterized by progressive degeneration of photoreceptors in the retina [7578]. Complete blindness in most cases proves that humans lack a homeostatic mechanism to replace lost photoreceptors [79].

The earliest interventions used autologous tissue resident stem cells such as RPE cell suspensions or RPE-choroid sheets to improve vision of patients affected by age-related macular degeneration via subretinal translocation [80]. Other sources of stem or progenitors cells from extraocular tissues such as hematopoietic stem cells (HSCs) [8183], dental pulp stem cells (DPSCs) [68], hair follicle stem cells (HFSCs) [84], mesenchymal stem cells (MSCs) [76, 8589], and induced pluripotent stem cells (iPSCs) [9092] have been explored for regenerating retinal neurons, corneal or conjunctival epithelial cells, and the RPE. The reason for using these stem cells is their capability to form neural progenitor cells or mature optic cells and the release of trophic factors important for reparative mechanism (Table 1 [76, 82, 83, 8588, 90, 91, 9399]). The manipulation of these cells raises less debate over moral and ethical issues than the use of ESCs [93] and fetal stem cells [100, 101]. Moreover, the eye is a suitable target organ for stem cell transplantation because it is immune-privileged, and strict containment by the blood-retinal barrier will disable the emigration of possibly maltransformed injected cells to extraocular tissues [102].

Figure 4 shows microcomputed tomography images to track the injected human Whartons jelly-derived MSCs (hWJ-MSCs) in a Retinitis Pigmentosa rat model [103]. The gold-loaded hWJ-MSC remained in the eye with no systemic migration to other organs detected on day 70 after injection. This study indicated that the injected MSCs were confined to the subretinal layer of experimented eyes and that no systemic migration occurred in the rat model [103]. Figure 5 shows rat retinal cell phenotypes exhibiting modest level of human MSCs marker, as observed by confocal microscopy. Colocalization of stem 121 (mesenchymal stem cell marker, red color in Figure 5) with rhodopsin (green), GFAP (Mller glial cells, green color in Figure 5), and PKC- (bipolar cells, green color in Figure 5) [103] was found, implying that MSCs could have differentiated into specific retinal cell phenotypes upon activation by cytokines released by the dying cells or fused with the degenerating cells to rescue tissue death [104, 105]. It is noteworthy that other studies have also demonstrated differentiation of human Whartons jelly-derived MSCs into neurons [106], glia [107], and retinal progenitor cells [108]. Hence, introduction of hWJ-MSCs might be beneficial in inducing certain level of cell repair or regeneration in retinal degeneration.

However, the most significant barrier for successful visual restoration has been the failure of these neuron-derived stem cells to integrate into the retinal circuitry. In central nervous system, stem cells and its neuron derivatives were reported to successfully integrate into the host neural circuitry [109112]. On the contrary, the integration of transplanted cells might be influenced by the molecular predisposition in the damaged eye tissues, which could vary even between different regions [111] and the ontogenetic stage of transplanted neurons [104]. MacLaren et al. first demonstrated that physiologically older retinal tissues showed predilection and tissue acceptance to later ontogenetic stage of transplanted retinal cells, that is, immature postmitotic photoreceptors over neural progenitor cells [104]. Human ESCs-directed differentiated retinal cells could migrate and integrate into the retinal layer and form synapses in transgenic mice following intravitreal injection at birth or postnatal day 1 [113]. Conversely, there is also a report that ESCs-derived neural stem cells showed lesser migration and integration in the retina. To prove that ontogenetic stage of transplanted neurons would also determine the level of integration, West et al. used three-dimensional culture of mouse ESCs with overexpression of Rax genes to direct generation of retinal neuron cells at different time points to establish an equivalent retinal developmental stage for a retinal cell integration study [114]. Unfortunately, their results were not able to prove that the transplantation of photoreceptors at the late ontogenetic stage has better integration into the retinal layer. However, a significant reduction of tumorigenic formation in the retina was observed when photoreceptors were used than when ESCs were used. The difference in the gene expression profile of the different ontogenetic stage of stem cells or progenitors may not mimic the native characteristics of retinal neurons, hence, an incomplete integration into the retinal circuitry. The characteristics of transplanted cells can be significantly affected by the choice of culture methods [115]. Generally, future studies should widen focus on the determination of geographical protein expression in different ocular disorders and identification of similarities in gene expression, rather than mere dependence on morphological observation or in vitro functional studies. It is hoped that these efforts would provide clue on tissue predilection over specific stem cells or its neuron derivatives for maximum therapeutic efficacy.

There is also a suggestion that concomitant transplantation of stem cells with telocytes may help restore the microenvironment. Telocytes are interstitial cells that reside in close contact with stem cells (Figure 6) and may be responsible for the transfer of bioactive molecules (nutrients and paracrine factors) among neighboring cells such as nerve cells and blood vessels [116]. The presence of telocytes has been reported in skeletal muscle [116], uterus [117], skin [118], heart [119], digestive tract [120], lung [121], and iris and uvea of mouse eyes [122].

Advanced techniques have also used a denuded amniotic membrane as a substratum for epithelial cell culture and stratification [123] and used cord blood serum to replace xenobiotic material [124] for conjunctival or corneal transplant. Recently, there is also research effort in developing a new mode of delivery of stem cells through direct application of contact lenses on the ocular surface [125]. Observation of successful stratified epithelization on a corneal wound bed in a rabbit model of limbal stem cell deficiency following application of modified-contact lens (with plasma polymer with high acid functional group) cultured with limbal cells has high clinical indications, suggesting that surgery for corneal transplant may not be needed in the future [125]. Laboratory procedures are getting standardized with simple protocol for culturing limbal cells to adopt with many cell sources [126]. Markers like Keratin 14 is used to map the distribution of precursor cells of cornea and suggested for corneal renewal with stem cells for alternative regenerative therapy [127]. Also to strengthen the universal standard in techniques, good manufacturer practice based on UK facilities on ocular surface reconstruction is suggested for use outside the UK [128].

Retinal degeneration is a medical condition that affects the health and welfare of adults and children in the developed world. It represents a group of blinding diseases that include age-related macular disease, glaucoma, optic neuropathies, and retinal vascular complication. Many clinical trials were performed to develop treatments for these diseases. However, it was reported that those approaches were still unable to entirely cure the disease. Interestingly, a stem cell-based treatment shows an extraordinary potential to rectify some of these diseases. In the past few years, studies strongly propose that stem-cell-based therapy has the ability to correct defective function of retina photoreceptors [114, 126], ganglion cells, retinal pigment epithelium (RPE) [129, 130], and optic nerve [131, 132].

Retinal Pigment Epithelial Cells (RPE) and Age-Related Macular Disease (ARMD). The macula enables people to read, process faces, and drive. Degeneration of the RPE leads to malformation at the macular area of the central vision at the initial phase and eventually progressive loss of central vision. This medical condition, known as age-related macular degeneration (ARMD), contributes to the highest cases of blindness in the elderly population globally [92, 133].

ARMD could be present either in wet or in dry forms (wet and dry ARMD) [134]. Wet ARMD manifests as neovascularization, which can be successfully managed with monthly inoculation of antiangiogenic drugs such as Lucentis [135]. Although effective in treating wet ARMD, the monthly injection into the eye causes discomfort and inconvenience to the patient and is expensive [136]. In contrast, dry ARMD presents as drusenoid aggregates under the basal side of the RPE layer at the early phase. These aggregations will lead to geographic atrophy with pronounced loss of the RPE and photoreceptors at later stage. Most of the ARMD cases (80 to 90% patients) occurred due to the dry form as no effective treatments have been found to date.

Currently, clinical trials using RPE-derived human from ESCs and other stem cell-derived therapy are ongoing and becoming a promising approach for the treatment of ARMD. Several companies and institutions are actively involved in stem cell research to treat various ocular diseases, including institutions in Japan, USA, Europe, South America, China, Iran, Taiwan, and South Korea. To date, stem cell therapies have been administered to over 200 patients globally. Schwartz and his colleagues [72, 130] performed clinical trials on patients affected by dry ARMD (NCT01344993) and Stargardts macular dystrophy (NCT01345006) [72]. In these trials, the researchers injected 50,000 to 200,000 hESC-derived retinal pigment epithelial cells into the worst-affected retina of the patients. Figure 7 shows fundus images taken from the patients following transplantation with hESCs-derived retinal pigment epithelial cells. There were increases in the area size and subretinal pigmentation of patches of transplanted cells in 72% of the treated patients with dry ARMD and Stargardts macular dystrophy at 315 months later [72]. Figures 7(b) and 7(c) showed that the patch of transplanted cells, which were present typically at the boundary of atrophic lesion on the eye of dry ARMD patients, became larger and more pigmented within 6 months. Meanwhile, in a patient with Stargardts macular dystrophy, patches of pigmented cells were found around the boundary of baseline atrophy in retinal pigment epithelium layer (Figure 7(e)) and appeared more prominent after 12 months of transplantation (Figure 7(f)). Figure 7(g) shows preoperative image of another Stargardts macular dystrophic patient with a large central area of atrophy. Six months later after transplantation, the superior half of the atrophic lesion was totally filled in by the transplanted retinal pigment epithelial cells (Figure 7(h)). The filled area became larger in size and more pigmented sites were seen after 15 months of transplantation (Figure 7(i)) [72]. It is important to emphasize that the vision-related quality of life was enhanced in both patients of atrophic ARMD and Stargardts macular dystrophy. None of the patients have reported signs of abnormal tissue formation at either the local or ectopic site of injections or immune rejections even four months after injection [72].

It should be mentioned that Professor Takahashis group [137141] at Kyoto University has been studying the transplantation of retinal pigmented epithelium cells into ARMD patients, which are differentiated from human iPSCs reprogrammed from patient cells. The tissue has maintained its brownish color, which is a sign that it has not been attacked by the immune system [142].

Ocata Therapeutics (formerly known as Advanced Cell Technology) has sponsored the trials at the Jules Stein Eye Institute, Massachusetts Eye & Ear, Wills Eye Institute and Bascom Palmer Eye Institute. Neurotech Pharmaceuticals (NCT00447954) has conducted a trial using encapsulated, modified human RPE cells to express ciliary neurotrophic factor for intraocular implantation into ARMD patients. Another report (NCT01518127) shows that Siqueira has been engaged in wet ARMD treatment using bone marrow-derived stem cells in a prospective phase I/II clinical trial [143]. Unfortunately, the complete outcomes have not yet been posted in the clinical trial registry of US National Institutes of Health (ClinicalTrials.gov) despite the fact that the trial was ended in December 2015. Other institutes, such as CHA Bio & Diostech (NCT01674829), Janssen R&D (NCT01226628), University of California, Davis Eye Center (NCT01736059) [83], University College London, Moorfields Eye Hospital (NCT01691261) [144], Hollywood Eye Institute (NCT02024269), and Stem Cells Inc. (NCT01632527) [145], were also engaged in stem cell therapy for ARMD.

Glaucoma is the most common neurodegenerative disease in the inner part of retina. Prevalence models predict an increase of glaucoma incidence to 79.6 million by 2020 worldwide, a jump from 60.5 million in 2010 [11]. Similar to other neurodegenerative disorders, the loss of the nerve cell population from the central nervous system can be used to predict the risk of glaucoma. Additionally, signs of glutamate toxicity, oxidative stress, impaired axonal transport, and reactive glial changes are also well-characterized in glaucoma [146, 147]. However, in glaucoma, retinal ganglion cells (RGC) predominantly die, which leads to the degeneration of the optic nerve and disconnecting the communication of signals from the retina to the brain.

Increases in age and raised intraocular pressure can lead to the occurrence of glaucoma. Diagnosis and prescription of a suitable treatment for glaucoma can be too late as patients may present asymptomatically until the end stage of the disease, which results in significant loss of visual function. Clinically verified treatments such as medication and eye surgery could delay the development of the glaucoma by reducing intraocular pressure but fail to halt the disease entirely to prevent loss of vision [148]. As of the date of this review, two registered clinical trials (NCT01920867 and NCT02330978) are recruiting patients for glaucoma treatment with bone marrow-derived mesenchymal stem cells. The safety of autologous stem cells derived from adipose tissue is also currently being tested in a phase I/II clinical trial (NCT02144103) for glaucomatous neurodegeneration. Additionally, Dr. Goldberg at the University of California has tested the treatment of ciliary neurotrophic factor on primary open angle glaucoma patients at the Bascom Palmer Eye Institute, University of Miami (NCT01408472). Several preclinical models have proven that ciliary neurotrophic factor could augment the survival and renewability of retinal ganglion cells [149, 150].

The optic nerve can lead to various pathologies due to intraorbital, intracranial, intrinsic, or systemic disorders. Optic nerve diseases could also lead to life- and vision-threatening conditions [151]. Neural loss from the optic nerve is a frequently occurring, irreversible blinding pathology that involves optic light-sensing tissue. Similar to the brain, the eye, which is a part of the central nervous system, will not be able to restore neuron loss after the occurrence of disease [148]. The patterns of optic nerve diseases provide information to the researcher to help understand the fundamental pathological activity and establish a method to enhance advanced detection and treatment strategies [148]. Recently, Dr. Jamadar worked in a clinical trial (NCT01834079) at Chaitanya Hospital, Pune, to evaluate the safety and efficacy of using bone marrow-derived autologous cells for treating optic nerve disease. It is hoped that the primary outcome of reducing degeneration of the optic nerve will also lead to improvement in visual function and decreased intracranial hypertension. Neurotech Pharmaceuticals also used similar RPE cell implants to administer CNTF to patients with optic nerve stroke in a separate phase I clinical trial (NCT01411657).

Retinal diseases other than the major ocular diseases discussed above also cause problems. These diseases include retinal detachment and retinal vascular complications. Retinal detachment is a medical condition in which the retina separates from the back of the eye. In a case report by Wilkes et al. [152], one in 10,000 people faces this problem per year. As the detachment period increases, the visual recovery reduces at an exponential rate after macula-off retinal detachment [153]. With modern surgical techniques, such as scleral buckling, pneumatic retinopexy, and pars plana vitrectomy, we can anticipate more than a 90% success rate for anatomical repair [154]. Although these treatments show positive results anatomically, the visual result still remains displeasing due to the enduring functional injury to the macula [155].

Clinical trials for treating retinal detachment began in the 1980s. A report by Brinton states that of 106 cases of eye trauma, 55 eyes (52%) attained final visual acuity of 20/100 after surgery [156]. The researchers also found that patients who engaged in later vitrectomy did not achieve a better final visual outcome than those who engaged in early vitrectomy within 14 days of impairment. In a separate study, Burton found that 53% of patients who experienced macula-off retinal detachments and underwent early surgery reached visual acuity of 20/20 to 20/50 [153]. However, patients with long-standing detachments were not able to reap functional benefits after surgery. A case reported by Suzuki and Hirose in 1997 states that after 3 months of total retinal detachment, vision was recovered in a patient with no light perception (NLP) [157]. After undergoing two surgeries, the patient recovered counting fingers (CF) vision. The scientists hypothesized that some retinal receptors were capable of eluding the failure. Although all of these trials showed a positive result in patient visual function recovery, the treatment is applicable to only early stage impairment and is costly and inconvenient. The use of stem cell-based therapy in retinal detachment cases might be one of the alternative treatments for early or late stage retinal detachment. For instance, fibrovascular scarring in ARMD, DR, ROP, and neovascular glaucoma [158] can be attenuated by introduction of MSCs. The scar tissue could prevent reattachment of retina [159]. MSCs could also neutralize reactive oxygen species in injured eye tissue and secrete various cytokines and growth factors including hepatocyte growth factor (HGF), interleukin 10, and adrenomedullin, which has antifibrotic properties [160].

Some of the commonly arising retinal diseases that lead to vision loss are associated with retinal vascular complications. Of these diseases, diabetic retinopathy, retinal vein occlusion (RVO), diabetic macular oedema (DMO), and proliferative diabetic retinopathy (PDR) are of definite epidemiological significance and lead to blindness. Diabetic retinopathy is the third most dominant source of profound visual function impairment and blindness, followed by RVO [161]. In addition to RVO and PDR, ischemic retinopathies are also familiar diseases involved in vasodegeneration. This situation leads to hypoxia, which provokes the release of cytokines and growth factor in neighboring tissues [162] and then leakage of blood vessels and neovascularization, which has a functionally negative effect on optics.

Intravitreal injections of anti-VEGF antibodies and corticosteroids or laser photocoagulation are the contemporary clinical treatments that help attenuate vascular leakage and macular oedema. However, these treatments cause undesirable side effects and do not resolve the fundamental pathology. The vasodegeneration that occurs in the retina is primarily due to the loss of endothelial cells, smooth muscle cells, and pericytes, finally resulting in vascular blockage and hypoxia [162]. An ongoing clinical trial (NCT02119689), which started since 2011, has aimed to study on the impaired function of endothelial progenitor cells in patients of diabetic retinopathy. Stitt et al. hypothesized that the introduction of vascular stem cells such as endothelial progenitor cells can recondition the retinal nerve diseases by repairing and restoring the damaged vessel [163]. EyeCyte Inc. develops endothelial progenitor cells for use as angiogenic therapy in response to clinical indications specific to retinal nerve diseases, particularly those of ischemic diseases [148, 164, 165]. Additionally, the University of Sao Paulo has sponsored Dr. Rubens trial using intravitreal injections of bone marrow-derived hematopoietic stem cells (CD34+ cells) for treating ischemic and diabetic retinopathies (NCT01518842). A subset of CD34+ hematopoietic stem cells, which are proangiogenic, could work in synergy with endothelial cells to repair damaged blood vessels.

Stem cell-based therapy holds an extraordinary prospective in improving the lives of people who suffer from visual disorders. Research in this area will continue to grow to develop new remedies in treating and preventing the problem of vision loss. Interestingly, stem cell-based therapy is not a one-stop general remedy; however, it carries a promising future in producing new biological elements used to treat vision loss.

The authors declare that there are no competing interests regarding the publication of this paper.

Padma Priya Sivan, Sakinah Syed, and Pooi-Ling Mok contributed equally to this paper.

This research was partially supported by the Fundamental Research Grants Scheme (FRGS), Ministry of Educations, Malaysia, under Grant no. 5524401. This work was also supported by the Putra Grant, Universiti Putra Malaysia, Malaysia (9436300), and Ministry of Science and Technology, Taiwan, under Grant no. 104-2221-E-008-107-MY3. Deanship of Scientific Research, College of Science Research Centre, King Saud University, and Kingdom of Saudi Arabia are also acknowledged.

Excerpt from:
Stem Cell Therapy for Treatment of Ocular Disorders - Hindawi

Overworked and stressed out? Look on the bright side. Some stress is good for you.

While too little stress can lead to boredom and depression, too much can cause anxiety and poor health. The right amount of acute stress, however, tunes up the brain and improves performance and health. iStock images.

You always think about stress as a really bad thing, but its not, said Daniela Kaufer, associate professor of integrative biology at the University of California, Berkeley. Some amounts of stress are good to push you just to the level of optimal alertness, behavioral and cognitive performance.

New research by Kaufer and UC Berkeley post-doctoral fellow Elizabeth Kirby has uncovered exactly how acute stress short-lived, not chronic primes the brain for improved performance.

In studies on rats, they found that significant, but brief stressful events caused stem cells in their brains to proliferate into new nerve cells that, when mature two weeks later, improved the rats mental performance.

I think intermittent stressful events are probably what keeps the brain more alert, and you perform better when you are alert, she said.

Kaufer, Kirby and their colleagues in UC Berkeleys Helen Wills Neuroscience Institute describe their results in a paper published April 16 in the new open access online journal eLife.

The UC Berkeley researchers findings, in general, reinforce the notion that stress hormones help an animal adapt after all, remembering the place where something stressful happened is beneficial to deal with future situations in the same place, said Bruce McEwen, head of the Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology at The Rockefeller University, who was not involved in the study.

Kaufer is especially interested in how both acute and chronic stress affect memory, and since the brains hippocampus is critical to memory, she and her colleagues focused on the effects of stress on neural stem cells in the hippocampus of the adult rat brain. Neural stem cells are a sort of generic or progenitor brain cell that, depending on chemical triggers, can mature into neurons, astrocytes or other cells in the brain. The dentate gyrus of the hippocampus is one of only two areas in the brain that generate new brain cells in adults, and is highly sensitive to glucocorticoid stress hormones, Kaufer said.

Brain cells called astrocytes (pink) appear to be key players in the response to acute stress. Stress hormones stimulate astrocytes to release fibroblast growth factor 2 (green), which in turn lead to new neurons (blue). Image by Daniela Kaufer & Liz Kirby.

Much research has demonstrated that chronic stress elevates levels of glucocorticoid stress hormones, which suppresses the production of new neurons in the hippocampus, impairing memory. This is in addition to the effect that chronically elevated levels of stress hormones have on the entire body, such as increasing the risk of chronic obesity, heart disease and depression.

Less is known about the effects of acute stress, Kaufer said, and studies have been conflicting.

To clear up the confusion, Kirby subjected rats to what, to them, is acute but short-lived stress immobilization in their cages for a few hours. This led to stress hormone (corticosterone) levels as high as those from chronic stress, though for only a few hours. The stress doubled the proliferation of new brain cells in the hippocampus, specifically in the dorsal dentate gyrus.

Kirby discovered that the stressed rats performed better on a memory test two weeks after the stressful event, but not two days after the event. Using special cell labeling techniques, the researchers established that the new nerve cells triggered by the acute stress were the same ones involved in learning new tasks two weeks later.

In terms of survival, the nerve cell proliferation doesnt help you immediately after the stress, because it takes time for the cells to become mature, functioning neurons, Kaufer said. But in the natural environment, where acute stress happens on a regular basis, it will keep the animal more alert, more attuned to the environment and to what actually is a threat or not a threat.

They also found that nerve cell proliferation after acute stress was triggered by the release of a protein, fibroblast growth factor 2 (FGF2), by astrocytes brain cells formerly thought of as support cells, but that now appear to play a more critical role in regulating neurons.

Corticosterone (green hexagons), a glucocorticoid hormone related to stress, stimulates astrocytes to release FGF2, which triggers the generation of new neurons from neural stem cells.

The FGF2 involvement is interesting, because FGF2 deficiency is associated with depressive-like behaviors in animals and is linked to depression in humans, McEwen said.

Kaufer noted that exposure to acute, intense stress can sometimes be harmful, leading, for example, to post-traumatic stress disorder. Further research could help to identify the factors that determine whether a response to stress is good or bad.

I think the ultimate message is an optimistic one, she concluded. Stress can be something that makes you better, but it is a question of how much, how long and how you interpret or perceive it.

The eLife paper was coauthored by UC Berkeley colleagues Sandra E Muroy, Wayne G. Sun and David Covarrubias of the Department of Molecular and Cell Biology; Megan J. Leong of the Helen Wills Neuroscience Institute; and Laurel A. Barchas of the Department of Integrative Biology. Kirby is now a post-doctoral fellow at Stanford University.

Kaufers research was funded by a BRAINS (Biobehavioral Research Awards for Innovative New Scientists) award from the National Institute of Mental Health of the National Institutes of Health (R01 MH087495) and the National Alliance for Research on Schizophrenia and Depression. Kirby was supported by fellowships from the California Institute for Regenerative Medicine and the U.S. Department of Defense.

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Researchers find out why some stress is good for you

Japanese stem cell researcher

Shinya Yamanaka ( , Yamanaka Shin'ya, born September 4, 1962) is a Japanese stem cell researcher and a Nobel Prize laureate.[2][3][4] He serves as the director of Center for iPS Cell (induced Pluripotent Stem Cell) Research and Application and a professor at the Institute for Frontier Medical Sciences at Kyoto University; as a senior investigator at the UCSF-affiliated Gladstone Institutes in San Francisco, California; and as a professor of anatomy at University of California, San Francisco (UCSF). Yamanaka is also a past president of the International Society for Stem Cell Research (ISSCR).

He received the 2010 BBVA Foundation Frontiers of Knowledge Award in the biomedicine category, the 2011 Wolf Prize in Medicine with Rudolf Jaenisch,[6] and the 2012 Millennium Technology Prize together with Linus Torvalds. In 2012, he and John Gurdon were awarded the Nobel Prize for Physiology or Medicine for the discovery that mature cells can be converted to stem cells.[7] In 2013, he was awarded the $3 million Breakthrough Prize in Life Sciences for his work.

Yamanaka was born in Higashisaka, Japan, in 1962. After graduating from Tennji High School attached to Osaka Kyoiku University,[8] he received his M.D. degree at Kobe University in 1987 and his Ph.D. degree at Osaka City University Graduate School in 1993. After this, he went through a residency in orthopedic surgery at National Osaka Hospital and a postdoctoral fellowship at the J. David Gladstone Institutes of Cardiovascular Disease, San Francisco.

Afterwards, he worked at the Gladstone Institutes in San Francisco, US, and Nara Institute of Science and Technology in Japan. Yamanaka is currently a professor at Kyoto University, where he directs its Center for iPS Research and Application. He is also a senior investigator at the Gladstone Institutes as well as the director of the Center for iPS Cell Research and Application.[9]

Between 1987 and 1989, Yamanaka was a resident in orthopedic surgery at the National Osaka Hospital. His first operation was to remove a benign tumor from his friend Shuichi Hirata, a task he could not complete after one hour when a skilled surgeon would have taken ten minutes or so. Some seniors referred to him as "Jamanaka", a pun on the Japanese word for obstacle.[10]

From 1993 to 1996, he was at the Gladstone Institute of Cardiovascular Disease. Between 1996 and 1999, he was an assistant professor at Osaka City University Medical School, but found himself mostly looking after mice in the laboratory, not doing actual research.[10]

His wife advised him to become a practicing doctor, but instead he applied for a position at the Nara Institute of Science and Technology. He stated that he could and would clarify the characteristics of embryonic stem cells, and this can-do attitude won him the job. From 19992003, he was an associate professor there, and started the research that would later win him the 2012 Nobel Prize. He became a full professor and remained at the institute in that position from 20032005. Between 2004 and 2010, Yamanaka was a professor at the Institute for Frontier Medical Sciences.[11] Currently, Yamanaka is the director and a professor at the Center for iPS Cell Research and Application at Kyoto University.

In 2006, he and his team generated induced pluripotent stem cells (iPS cells) from adult mouse fibroblasts.[2] iPS cells closely resemble embryonic stem cells, the in vitro equivalent of the part of the blastocyst (the embryo a few days after fertilization) which grows to become the embryo proper. They could show that his iPS cells were pluripotent, i.e. capable of generating all cell lineages of the body. Later he and his team generated iPS cells from human adult fibroblasts,[3] again as the first group to do so.A key difference from previous attempts by the field was his team's use of multiple transcription factors, instead of transfecting one transcription factor per experiment. They started with 24 transcription factors known to be important in the early embryo, but could in the end reduce it to 4 transcription factors Sox2, Oct4, Klf4 and c-Myc.[2]

The 2012 Nobel Prize in Physiology or Medicine was awarded jointly to Sir John B. Gurdon and Shinya Yamanaka "for the discovery that mature cells can be reprogrammed to become pluripotent."[12]

There are different types of stem cells.

These are some types of cells that will help in understanding the material.

Theoretically patient-specific transplantations possible

Much research done

Immune rejection reducible via stem cell bank

Pluripotent

Abnormal aging

No immune rejectionSafe (clinical trials)

The prevalent view during the early 20th century was that mature cells were permanently locked into the differentiated state and cannot return to a fully immature, pluripotent stem cell state. It was thought that cellular differentiation can only be a unidirectional process. Therefore, non-differentiated egg/early embryo cells can only develop into specialized cells. However, stem cells with limited potency (adult stem cells) remain in bone marrow, intestine, skin etc. to act as a source of cell replacement.[13]

The fact that differentiated cell types had specific patterns of proteins suggested irreversible epigenetic modifications or genetic alterations to be the cause of unidirectional cell differentiation. So, cells progressively become more restricted in the differentiation potential and eventually lose pluripotency.[14]

In 1962, John B. Gurdon demonstrated that the nucleus from a differentiated frog intestinal epithelial cell can generate a fully functional tadpole via transplantation to an enucleated egg. Gurdon used somatic cell nuclear transfer (SCNT) as a method to understand reprogramming and how cells change in specialization. He concluded that differentiated somatic cell nuclei had the potential to revert to pluripotency. This was a paradigm shift at the time. It showed that a differentiated cell nucleus has retained the capacity to successfully revert to an undifferentiated state, with the potential to restart development (pluripotent capacity).

However, the question still remained whether an intact differentiated cell could be fully reprogrammed to become pluripotent.

Shinya Yamanaka proved that introduction of a small set of transcription factors into a differentiated cell was sufficient to revert the cell to a pluripotent state. Yamanaka focused on factors that are important for maintaining pluripotency in embryonic stem (ES) cells. This was the first time an intact differentiated somatic cell could be reprogrammed to become pluripotent.

Knowing that transcription factors were involved in the maintenance of the pluripotent state, he selected a set of 24 ES cell transcriptional factors as candidates to reinstate pluripotency in somatic cells. First, he collected the 24 candidate factors. When all 24 genes encoding these transcription factors were introduced into skin fibroblasts, few actually generated colonies that were remarkably similar to ES cells.Secondly, further experiments were conducted with smaller numbers of transcription factors added to identify the key factors, through a very simple and yet sensitive assay system.Lastly, he identified the four key genes. They found that 4 transcriptional factors (Myc, Oct3/4, Sox2 and Klf4) were sufficient to convert mouse embryonic or adult fibroblasts to pluripotent stem cells (capable of producing teratomas in vivo and contributing to chimeric mice).

These pluripotent cells are called iPS (induced pluripotent stem) cells; they appeared with very low frequency. iPS cells can be selected by inserting the b-geo gene into the Fbx15 locus. The Fbx15 promoter is active in pluripotent stem cells which induce b-geo expression, which in turn gives rise to G418 resistance; this resistance helps us identify the iPS cells in culture.

Moreover, in 2007, Yamanaka and his colleagues found iPS cells with germline transmission (via selecting for Oct4 or Nanog gene). Also in 2007, they were the first to produce human iPS cells.

Some issues that current methods of induced pluripotency face are the very low production rate of iPS cells and the fact that the 4 transcriptional factors are shown to be oncogenic.

In July 2014, a scandal regarding the research of Haruko Obokata was connected to Yamanaka. She could not find the lab notes from the period in question[15] and was made to apologise.[16][17]

Since the original discovery by Yamanaka, much further research has been done in this field, and many improvements have been made to the technology. Improvements made to Yamanaka's research as well as future prospects of his findings are as follows:

Yamanaka's research has "opened a new door and the world's scientists have set forth on a long journey of exploration, hoping to find our cells true potential."[18]

In 2013, iPS cells were used to generate a human vascularized and functional liver in mice in Japan. Multiple stem cells were used to differentiate the component parts of the liver, which then self-organized into the complex structure. When placed into a mouse host, the liver vessels connected to the hosts vessels and performed normal liver functions, including breaking down of drugs and liver secretions.[19]

In 2022, Yamanaka factors were shown to effect age related measures in aged mice.[20]

In 2007, Yamanaka was recognized as a "Person Who Mattered" in the Time Person of the Year edition of Time Magazine.[21] Yamanaka was also nominated as a 2008 Time 100 Finalist.[22] In June 2010, Yamanaka was awarded the Kyoto Prize for reprogramming adult skin cells to pluripotential precursors. Yamanaka developed the method as an alternative to embryonic stem cells, thus circumventing an approach in which embryos would be destroyed.

In May 2010, Yamanaka was given "Doctor of Science honorary degree" by Mount Sinai School of Medicine.[23]

In September 2010, he was awarded the Balzan Prize for his work on biology and stem cells.[24]

Yamanaka has been listed as one of the 15 Asian Scientists To Watch by Asian Scientist magazine on May 15, 2011.[25][26] In June 2011, he was awarded the inaugural McEwen Award for Innovation; he shared the $100,000 prize with Kazutoshi Takahashi, who was the lead author on the paper describing the generation of induced pluripotent stem cells.[27]

In June 2012, he was awarded the Millennium Technology Prize for his work in stem cells.[28] He shared the 1.2 million euro prize with Linus Torvalds, the creator of the Linux kernel. In October 2012, he and fellow stem cell researcher John Gurdon were awarded the Nobel Prize in Physiology or Medicine "for the discovery that mature cells can be reprogrammed to become pluripotent."[29]

Yamanaka practiced judo (2nd Dan black belt) and played rugby as a university student. He also has a history of running marathons. After a 20-year gap, he competed in the inaugural Osaka Marathon in 2011 as a charity runner with a time of 4:29:53. He took part in Kyoto Marathon to raise money for iPS research since 2012. His personal best is 3:25:20 at 2018 Beppu-ita Marathon.

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Shinya Yamanaka - Wikipedia

Specially treated stem cells derived from a single individual have been successfully implanted into that same individuals eyes in a first-of-its-kind clinical trial testing ways to treat advanced dry age-related macular degeneration (AMD).

The therapy, currently in its first phase of testing to ensure that its safe for humans, involves harvesting and processing a persons blood cells and using them to replace the persons retinal cells that had succumbed to AMD, a leading cause of vision loss globally.

The procedure was performed by researchers from the National Eye Institute (NEI), a branch of the National Institutes of Health in Bethesda, Maryland, and from the Wilmer Eye Institute at Johns Hopkins School of Medicine in Baltimore. The NIH researchers have been working on the new treatment for a decade.

The scientists, who previously demonstrated the safety and effectiveness of the therapy in rats and pigs, took blood cells from the patient and, in the laboratory, converted them into patient-derived induced pluripotent stem (iPS) cells. These immature, undifferentiated cells have no assigned function in the body, which means they can assume many forms. The researchers programmed these particular iPS cells to become retinal pigment epithelial (RPE) cells, the type that die in AMD and lead to late-stage dry AMD.

In healthy eyes, RPE cells supply oxygen to photoreceptors, the light-sensing cells in the retina at the back of the eyeball. The death of RPE cells virtually dooms the photoreceptors, resulting in vision loss. The idea behind the new therapy is to replace dying RPE cells with patient-derived induced iPS ones, strengthening the health of the remaining photoreceptors.

Before being transplanted, the iPS-derived cells were grown in sheets one cell thick on a biodegradable scaffold designed to promote their integration into the retina. The researchers positioned the resulting patch between atrophied host RPE cells and the photoreceptors using a specially created surgical tool.

The patient received the transplanted cells during the summer and will be followed for a year as researchers monitor overall eye health, including retina stability, and whether any inflammation or bleeding develop, says Kapil Bharti, PhD, a senior investigator at the NEI and for the clinical trial.

Safety data are critical for any new drug, says Gareth Lema, MD, PhD, a vitreoretinal surgeon at New York Eye & Ear Infirmary, a division of the Mount Sinai Health System. Stem cells have added complexity in that they are living tissue, Dr. Lema says. Precise differentiation is necessary for them to fulfill their intended therapeutic effect and not cause harm."

This therapy also requires a surgical procedure to implant the cells, Lema says, adding that its an exquisitely elegant surgery, but introduces further risk of harm. For those reasons, he says, Patients must know that ocular stem cell therapies should only be attempted within the regulated environment of a nationally registered clinical trial.

The rules of a clinical trial dont generally allow specifics to be discussed this early in the process, says Dr. Bharti. Announcing that we were able to successfully transplant the cells now hopefully allows us to recruit more patients, since we can take up to 12 in this phase, he says. We also hope that it will give some optimism to patients with dry AMD and to researchers studying it.

It took seven months to develop the implanted cells, says Bharti, and although the federal Food and Drug Administration (FDA) approved the clinical trial in 2019, the onset of the COVID-19 pandemic delayed the start by two years, he says.

Macular degeneration comprises several stages of disease within the macula, the critical portion of the retina responsible for straight-ahead vision. Aging causes retinal cells to deteriorate, generating debris, or drusen, within the macula, setting the stage for early (aka dry) AMD. Geographic atrophy represents a more advanced stage. If the disease progresses to the relatively rare wet AMD, so named for the leaking of blood into the macula, central vision can be snuffed out.

Risk of AMD increases with age, particularly among people who are white, have a history of smoking, or have a family history of the disease.

Treatment to slow wet AMDs progression includes eye injections with anti-VEGF (or VEGF-A for vascular endothelial growth factor antagonists), a medication that halts the growth of unstable, leaky blood vessels in the eye. Some people may undergo photodynamic therapy, which combines injections and laser treatments.

Currently, there is no cure for dry AMD; it cant be reversed. Nor are there treatments to reliably stop its onset or progression for everyone at every stage of the disease. (Research has confirmed that a specialized blend of vitamins and minerals, available over the counter as AREDS, or Age-Related Eye Disease Studies supplements, reduces the risk of AMDs progression from intermediate to advanced stages.)

There are other, ongoing clinical trials for the treatment of dry AMD. Regenerative Patch Technologies, in Menlo Park, California, for example, is a little further along in testing a different stem cell treatment. Patients have been followed for three years, and 27 percent have shown vision improvement, says Jane Lebkowski, PhD, the companys president. There are a number of AMD clinical trials ongoing in the U.S., and patients should ask their ophthalmologists about trials that might be appropriate.

ClinicalTrials.gov, the NIHs clinical trials database, lists close to 300 AMD clinical trials at various stages in the United States.

Ferhina Ali, MD, MPH, a retinal specialist at the Westchester Medical Center in Valhalla, New York, who isnt involved in the trial, describes the newest stem cell therapy as elegant and pioneering. These are early stages but there is tremendous potential as a first-in-kind surgically implanted stem cell therapy and as a way to achieve vision gains in dry macular degeneration, Dr. Ali says.

Bharti says that in laboratory animals the implanted cells behaved as retinal cells should maintaining the retinas integrity. Over the next few years, he and his colleagues will determine whether they function effectively in humans.

Does that mean, however, that the same AMD disease process that destroyed the original retinal cells could destroy the transplanted ones? It takes 40 to 60 years to damage human cells, Bharti says, and if we get that long with the transplanted cells, well take it.

Continued here:
Implanting a Patient's Own Reprogrammed Stem Cells Shows Early Positive ...

(SACRAMENTO)

Three babies have been born after receiving the worlds first spina bifida treatment combining surgery with stem cells. This was made possible by a landmark clinical trial at UC Davis Health.

The one-of-a-kind treatment, delivered while a fetus is still developing in the mothers womb, could improve outcomes for children with this birth defect.

Launched in the spring of 2021, the clinical trial is known formally as the CuRe Trial: Cellular Therapy for In Utero Repair of Myelomeningocele. Thirty-five patients will be treated in total.

The three babies from the trial that have been born so far will be monitored by the research team until 30 months of age to fully assess the procedures safety and effectiveness.

The first phase of the trial is funded by a $9 million state grant from the states stem cell agency, the California Institute for Regenerative Medicine (CIRM).

This clinical trial could enhance the quality of life for so many patients to come, said Emily, the first clinical trial participant who traveled from Austin, Tex. to participate. Her daughter Robbie was born last October. We didnt know about spina bifida until the diagnosis. We are so thankful that we got to be a part of this. We are giving our daughter the very best chance at a bright future.

Spina bifida, also known as myelomeningocele, occurs when spinal tissue fails to fuse properly during the early stages of pregnancy. The birth defect can lead to a range of lifelong cognitive, mobility, urinary and bowel disabilities. It affects 1,500 to 2,000 children in the U.S. every year. It is often diagnosed through ultrasound.

While surgery performed after birth can help reduce some of the effects, surgery before birth can prevent or lessen the severity of the fetuss spinal damage, which worsens over the course of pregnancy.

Ive been working toward this day for almost 25 years now, said Diana Farmer, the worlds first woman fetal surgeon, professor and chair of surgery at UC Davis Health and principal investigator on the study.

As a leader of the Management of Myelomeningocele Study (MOMS) clinical trial in the early 2000s, Farmer had previously helped to prove that fetal surgery reduced neurological deficits from spina bifida. Many children in that study showed improvement but still required wheelchairs or leg braces.

Farmer recruited bioengineer Aijun Wang specifically to help take that work to the next level. Together, they launched theUC Davis Health Surgical Bioengineering Laboratoryto find ways to use stem cells and bioengineering to advance surgical effectiveness and improve outcomes. Farmer also launched the UC Davis Fetal Care and Treatment Centerwith fetal surgeon Shinjiro Hirose and the UC DavisChildrens Surgery Center several years ago.

Farmer, Wang and their research team have been working on their novel approach using stem cells in fetal surgery for more than 10 years. Over that time, animal modeling has shown it is capable of preventing the paralysis associated with spina bifida.

Its believed that the stem cells work to repair and restore damaged spinal tissue, beyond what surgery can accomplish alone.

Preliminary work by Farmer and Wang proved that prenatal surgery combined with human placenta-derived mesenchymal stromal cells, held in place with a biomaterial scaffold to form a patch, helped lambs with spina bifida walk without noticeable disability.

When the baby sheep who received stem cells were born, they were able to stand at birth and they were able to run around almost normally. It was amazing, Wang said.

When the team refined their surgery and stem cells technique for canines, the treatment also improved the mobility of dogs with naturally occurring spina bifida.

A pair of English bulldogs named Darla and Spanky were the worlds first dogs to be successfully treated with surgery and stem cells. Spina bifida, a common birth defect in this breed, frequently leaves them with little function in their hindquarters.

By their post-surgery re-check at 4 months old, Darla and Spanky were able to walk, run and play.

When Emily and her husband Harry learned that they would be first-time parents, they never expected any pregnancy complications. But the day that Emily learned that her developing child had spina bifida was also the day she first heard about the CuRe trial.

For Emily, it was a lifeline that they couldnt refuse.

Participating in the trial would mean that she would need to temporarily move to Sacramento for the fetal surgery and then for weekly follow-up visits during her pregnancy.

After screenings, MRI scans and interviews, Emily received the life-changing news that she was accepted into the trial. Her fetal surgery was scheduled for July 12, 2021, at 25 weeks and five days gestation.

Farmer and Wangs team manufactures clinical grade stem cells mesenchymal stem cells from placental tissue in the UC Davis Healths CIRM-funded Institute for Regenerative Cures. The cells are known to be among the most promising type of cells in regenerative medicine.

The lab is aGood Manufacturing Practice(GMP) Laboratory for safe use in humans. It is here that they made the stem cell patch for Emilys fetal surgery.

Its a four-day process to make the stem cell patch, said Priya Kumar, the scientist at the Center for Surgical Bioengineering in the Department of Surgery, who leads the team that creates the stem cell patches and delivers them to the operating room. The time we pull out the cells, the time we seed on the scaffold, and the time we deliver, is all critical.

During Emilys historic procedure, a 40-person operating and cell preparation team did the careful dance that they had been long preparing for.

After Emily was placed under general anesthetic, a small opening was made in her uterus and they floated the fetus up to that incision point so they could expose its spine and the spina bifida defect. The surgeons used a microscope to carefully begin the repair.

Then the moment of truth: The stem cell patch was placed directly over the exposed spinal cord of the fetus. The fetal surgeons then closed the incision to allow the tissue to regenerate.

The placement of the stem cell patch went off without a hitch. Mother and fetus did great! Farmer said.

The team declared the first-of-its-kind surgery a success.

On Sept. 20, 2021, at 35 weeks and five days gestation, Robbie was born at 5 pounds, 10 ounces, 19 inches long via C-section.

One of my first fears was that I wouldnt be able to see her, but they brought her over to me. I got to see her toes wiggle for the first time. It was so reassuring and a little bit out of this world, Emily said.

For Farmer, this day is what she had long hoped for, and it came with surprises. If Robbie had remained untreated, she was expected to be born with leg paralysis.

It was very clear the minute she was born that she was kicking her legs and I remember very clearly saying, Oh my God, I think shes wiggling her toes! said Farmer, who noted that the observation was not an official confirmation, but it was promising. It was amazing. We kept saying, Am I seeing that? Is that real?

Both mom and baby are at home and in good health. Robbie just celebrated her first birthday.

The CuRe team is cautious about drawing conclusions and says a lot is still to be learned during this safety phase of the trial. The team will continue to monitor Robbie and the other babies in the trial until they are 6 years old, with a key checkup happening at 30 months to see if they are walking and potty training.

This experience has been larger than life and has exceeded every expectation. I hope this trial will enhance the quality of life for so many patients to come, Emily said. We are honored to be part of history in the making.

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NEW YORK and SAN FRANCISCO, Oct. 10, 2022 /PRNewswire/ -- JDRF, the leading global type 1 diabetes (T1D) research and advocacy organization, together with the University of California, San Francisco (UCSF), announce the appointment of Qizhi Tang, Ph.D.,professor of surgery and director of the UCSF Transplantation Research Laboratory, as the new co-director of theJDRF Center of Excellence in Northern California. In her new role, Dr. Tang will co-lead the institution with Seung Kim, M.D., Ph.D., as the center works to deliver next-generation therapies and first-generation cures for T1D.

"Dr. Tang has been a key leader at the JDRF Center of Excellence in Northern California since its inception," said Esther Latres, JDRF assistant vice president of research. "Her experience in immunology, clinical transplantation, and beta cell replacement therapy will be an added asset as the center expands. The combined leadership of Dr. Tang and Dr. Kimwill undoubtedly accelerate research toward developing new approaches to generate highly functional islets and protect them from the immune system after transplantation."

JDRF announces Qizhi Tang, Ph.D., as the new co-director of the JDRF Center of Excellence in Northern California.

Dr. Tang joined the UCSF faculty in 2002 as an assistant professor of pathology and at the Diabetes Center, where she researched mechanisms of immune tolerance in mouse models of T1D. In 2007 Dr. Tang was appointed the director of the UCSF Transplantation Research Laboratory and joined the transplantation division in the Department of Surgery to lead basic and translational research in transplant immunology. In that role, she has built cross-disciplinary collaborative teams to rapidly translate laboratory discoveries into early-phase clinical trials.

"Dr. Tang is an outstanding, highly collaborative scientist and leader of scientific programs, and we are privileged to have her assume this important role," said Dr. Seung Kim, M.D., Ph.D., JDRF Center of Excellence in Northern California co-director. "Her focus on type 1 diabetes immune therapeutics and pathogenesis have been framed by productive studies, often at multiple institutions, and perfectly align with her leadership in the Center of Excellence. I am pleased to co-direct and collaborate with her."

"A confluence of knowledge and technology makes this an exciting time for T1D research," said Dr. Qizhi Tang. "The support of the JDRF Center of Excellence allows us to recruit talents to translate these research advances into therapies for type 1 diabetes. I am honored to have the opportunity to lead this effort."

The JDRF Center of Excellence in Northern California is a cure accelerator and high-impact partnership combining the scientific expertise of Stanford University and the University of California, San Francisco, within the collaborative structure and support that are hallmarks of JDRF. Investigators at the Center will seek to better understand and target the interactions between the immune system and beta cells, identify new strategies to protect these cells after transplantation, and deliver advanced stem cell-based cures for T1D.

Dr. Tang's tenure as co-director of the Center of Excellence begins immediately, taking over for Dr. Matthias Hebrok, who has been appointed as founding chair of the Center for Organoid Systems and Tissue Engineering (COS) at the Technical University of Munich (TUM) and Director of the new Institute for Diabetes and Organoid Technology (IDOT) at the Helmholtz Center, Germany.

"I have enjoyed being at UCSF for more than 22 years, and it has been a privilege to help build and co-direct the JDRF Center of Excellence in Northern California with the clear intent of finding new ways to treat patients living with type 1 diabetes," said Dr. Hebrok.

Dr. Hebrok's current research will continue under the leadership of Audrey Parent, Ph. D. assistant adjunct professor at the University of California, San Francisco. Dr. Parent has made seminal contributions to understanding how to generate and modify stem cell-derived beta cells to blunt the effects of the immune system.

For more information about The JDRF Center of Excellence in Northern California please visit, https://www.jdrf.org/impact/research/centers-of-excellence/northern-california/

For more information about the JDRF Center of Excellence program, visit https://www.jdrf.org/impact/research/centers-of-excellence/

About JDRF

JDRF's mission is to accelerate life-changing breakthroughs to cure, prevent and treat T1D and its complications. To accomplish this, JDRF has invested more than $2.5 billion in research funding since our inception. We are an organization built on a grassroots model of people connecting in their local communities, collaborating regionally for efficiency and broader fundraising impact, and uniting on a global stage to pool resources, passion, and energy. We collaborate with academic institutions, policymakers, and corporate and industry partners to develop and deliver a pipeline of innovative therapies to people living with T1D. Our staff and volunteers throughout the United States and our five international affiliates are dedicated to advocacy, community engagement, and our vision of a world without T1D. For more information, please visit jdrf.org or follow us on Twitter (@JDRF), Facebook (@myjdrf), and Instagram (@jdrfhq).

About UCSF

University of California, San Francisco is the leading university exclusively focused on health. Through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in care delivery, UCSF is leading revolutions in health worldwide.

About Type 1 Diabetes (T1D)

T1D is an autoimmune condition that causes the pancreas to make very little insulin or none at all, leading to long-term complications which can include highs and lows in blood sugar; damage to the kidneys, eyes, nerves and heart; and even death if left untreated. It is one of the fastest-growing chronic health conditions. Many believe T1D is only diagnosed in childhood and early puberty, but diagnosis in adulthood is on the rise, and accounts for nearly 50% of all T1D diagnoses. The onset is sudden and nothing can be done to prevent it yetit is not related to diet or lifestyle. While its causes are not yet entirely understood, scientists believe that both genetic factors and environmental triggers are involved. There is currently no cure for T1D.

SOURCE JDRF

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JDRF Announces the Appointment of Qizhi Tang, Ph.D., as Co-Director of The JDRF Center of Excellence in Northern California - PR Newswire

In a recent lawsuit brought by the Food and Drug Administration (FDA), a California judge entered a judgment in favour of the California Stem Cell Treatment Center (CSCTC).

The decision was that the use of patients own stem cells to treat various diseases and conditions does not fall under the purview of the FDAs authority.

This is a massive win for private stem cell clinics. Critics say that the ruling by Judge Jesus Bernal of the Central District of California is regarded as flawed. They warn that it creates opportunities for unscrupulous for-profit private clinics to provide stem cell treatments that are scientifically unproven and potentially risky.

This decision was not entirely surprising. Earlier, Judge Bernal had ruled against requests by the FDA and the Department of Justice for a summary judgment (a decision entered by a judge on one party and against another party summarily, i.e., without a full trial).

The FDA injunction case was pursued against the CSCTC, the Cell Surgical Network Corporation and their founders, Dr Elliot Lander, a surgeon and board-certified urologist, and the late Dr Mark Berman, a board-certified otolaryngologist and cosmetic surgeon. Since 2010 CSCTC has performed stem cell treatments for thousands of patients. Its doctors remove fat tissue to isolate stem cells. The treatments use the patients own cells.

The FDA alleged that the defendants manufactured products without first obtaining FDAs approval for a new drug. The company responded that a patients stem cells are not drugs and are not subject to regulation by the FDA.

The court ruled that the CSCTCs treatments are surgical procedures and do not create a new drug. It declared: The adipose tissue Defendants remove from patients clearly consists of human cells. And whatever is injected back into patients as part of Defendants SVF Surgical Procedure and Expanded MSC Surgical Procedure certainly contains such cells.

The defendants SVF procedure but not the expanded MSC procedure qualifies for a surgical procedure exception.

The International Society for Cell & Gene Therapy (ISCT) said that the ruling will have negative consequences for the cell and gene therapy field and patients safety.

Its president, Jacques Galipeau, said: This ruling introduces regulatory uncertainty into the CGT market, and unscrupulous clinics prey on this uncertainty to market unproven interventions to patients. The ruling reinforces the imperative market need for informative resources that establish scientific consensus, standards, and best practices. ISCT will continue to work with FDA and other like-minded national and international organisations and regulatory agencies to achieve ISCTs mission to drive clinical translation of cell and gene therapies worldwide.

It is critical that the therapies provided by clinics are evidence-based and the FDA plays a crucial role in ensuring this.

Judge Bernals judgment also conflicts with an earlier decision on a similar case in Florida. In that case, the state district court awarded summary judgment against the defendants, US Stem Cell clinics.

Now there is regulatory uncertainty.

It is not clear whether the FDA will appeal against this controversial decision. I hope that it does. The grave worry is that some clinics may be encouraged by this court judgment and continue to market untested stem cell treatments to vulnerable patients.

Dr Patrick Foong is a senior law lecturer at Western Sydney University. His research interest lies in bioethics and health law.

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California court creates regulatory uncertainty over the FDA regulation of stem cell therapies - BioEdge

The dystopian universe of Blade Runner features replicants, or genetically bioengineered people with sci-fi powers, like super-strength and advanced intelligence, that far outstrip any ordinary individual (albeit with a limited lifespan). Their invention is considered a colossal feat of scientific achievement (and the basis for a pretty messed-up society).

But off of the silver screen, weve yet to come close to making any organism let alone a human entirely from scratch. Until now.

In a study published last month in the journal Nature, scientists in the U.S., U.K., and Israel successfully created a synthetic mouse embryo without using any eggs or sperm. Instead, they used an assortment of stem cells.

Compared to natural embryos maturing alongside them, these lab-grown counterparts developed similar features seen nearly nine days after fertilization, such as a beating heart, a very early-stage brain, and a gut tube before they abruptly halted growth.

Essentially, the big question that we are addressing in the lab is how do we start our lives? said Magdalena Zernicka-Goetz, the studys lead researcher and a stem cell biologist at the University of Cambridge and California Institute of Technology, during a press briefing.

When a sperm fertilizes an egg, the fusion sets off a cascade of changes that cause the single cell to multiply, specialize, and organize into distinct cell types, tissues, organs, and other structures that constitute a complete organism.

For the last several decades, scientists have tried recreating models of embryonic development in the lab to learn how the primordial phenomenon proceeds in real time. But this feat has proven extremely challenging. After all, we cant just peer into a live uterus in the lab to directly observe the microscopic goings-on.

Specifically, researchers dont know what exactly happens in the womb between around 14 days and a month into development, says Max Wilson, a molecular biologist at the University of California, Santa Barbara, who was not involved in the study.

During this mystery period, the brain gets built and the heart is laid down. Its called the black box of human development, he explains.

Recent efforts to untangle these mysteries have involved coaxing human embryonic stem cells into blastocysts, a thin-walled, hollow ball of dividing cells that gives rise to the embryo during natural development.

This blastoid method didnt exactly bring scientists closer to seeing how cells self-organize and specialize into organs. But in 2021, researchers at the Weizmann Institute of Science in Israel who also worked on the new Nature study developed a sort of mechanical womb (picture an axolotl tank la Frank Herberts Dune).

This device took seven grueling years of engineering. It included an incubator, which floated and spun the embryos in vials filled with special nutrient-rich liquid. Meanwhile, a ventilator provided oxygen and carbon dioxide, meticulously controlling the gasses flow and pressure.

With this setup, the Weizmann researchers managed to make stem cell-derived synthetic mouse embryos thrive in their artificial mommy for about six days until they managed to extend it further, according to a study published earlier this month in the journal Cell.

The embryos underwent gastrulation (when an early embryo transforms into a multilayered structure) over the course of eight and a half days, but then stalled for unknown reasons. (A mouse pregnancy lasts for about 20 days.)

But the experiment wasnt entirely a dud. It set the mammoth task for the latest study: to show it was entirely possible to grow mammalian embryos outside the uterus.

Zernicka-Goetz and her colleagues used embryonic stem cells, along with those that give rise to the placenta and yolk sac, to grow synthetic embryos.Jose A. Bernat Bacete/Moment/Getty Images

Zernicka-Goetz, one of the authors behind the new Nature study, has spent the last decade investigating ways to develop synthetic embryos. She said her lab only initially used embryonic stem cells to mimic early development.

But in 2018, she and her colleagues discovered that if they tossed in two other stem cells that give rise to the placenta (the organ that provides nutrients and removes wastes) and the yolk sac (a structure that provides nourishment during early development), the embryos were better prepared for self-assembly.

Heres the thing about science: theres always competition. After their 2018 Nature paper, Zernicka-Goetzs team was surprised when the Weizmann group came out with an incubator-ventilator system, along with later experiments that forged embryos without sperm or eggs just as they were attempting.

But science is also about collaboration. The two groups eventually teamed up to see whether combining their techniques could culminate in the life-creating golden ticket.

The results were impressive: Zernicka-Goetz and her colleagues watched the artificially wombed cells grow into synthetic embryoids without any sort of external modifications or guidance.

Compared to the natural mouse embryos that were grown separately, these embryonic mice went through the same stages of development up to eight and half days after fertilization (just like the Weizmann teams earlier work) which is equivalent to day 14 of human embryonic development.

The embryo model developed a head and heart parts of the body researchers were never able to study in vitro, said Zernicka-Goetz.

This is really the first demonstration of the forebrain in any models of embryonic development, and thats been a Holy Grail for the field, co-author David Glover, a research professor of biology and biological engineering at Caltech, said during the press briefing.

Zernicka-Goetzs team also tinkered with a gene called Pax6, which appears to be a key player in brain development and function. After removing Pax6 from the mouse stem cell DNA with the help of CRISPR, Zernicka-Goetz and her colleagues observed that the heads of these synthetic embryos didnt develop correctly, mimicking whats seen when natural embryos lack this gene.

In humans, rare mutations or deletions of Pax6 can lead to abnormal development of the fetus and death. They can also spur conditions like aniridia (absence of the eyes colored part, the iris) or Peters anomaly, which hinders the development of eye structures like the cornea.

Concocting synthetic embyros from human stem cells could prove a technical (and ethical) challenge.Westend61/Westend61/Getty Images

The detailed glimpse into early embryonic development could be a boon to human health. For instance, it could help scientists grasp why many pregnancies, whether naturally conceived or via assisted reproductive means, fail in the early trimester.

Zernicka-Goetz said the research might also advance regenerative medicine. It could help scientists learn how to make viable, full-functioning replacement organs for a transplant patient using their own stem cells (potentially eliminating the need for lifelong use of immunosuppressants).

Currently, we have a broad sense of organogenesis or the development of an organ from embryo to birth but we dont know all the microscopic steps and cellular interactions that culminate in a fully-fledged, functional organ.

The model system could aid the development of new drugs: It may reveal which medications are safe to take during pregnancy without harming the fetus. Now, researchers can potentially test them out on synthetic embryos, Zernicka-Goetz said.

This is an advance but at a very early stage of development, a rare event which while superficially looking like an embryo, bears defects which should not be overlooked, Alfonso Martinez Arias, a developmental biologist at Pompeu Fabra University in Spain who wasnt involved in the study, said in a press release.

One glaring challenge: While the synthetic mouse embryos appear identical to their natural counterparts, their stalled development at eight and a half days makes it tough to say whether theyd continue to grow right on course.

So despite its enormous potential, fashioning synthetic embryos from stem cells just isnt possible right now.

This blockade is not understood and needs to be overcome if one desires to grow mouse synthetic embryos past day eight, Christophe Galichet, a stem cell biologist at Francis Crick Institute in London who also wasnt involved in the new work, said in the same press release.

Since humans and mice dont exactly share all the same characteristics when it comes to embryonic development, the next step is to eventually concoct synthetic embryos from human stem cells.

That likely will prove complicated, more so ethically than technique-wise. But Wilson thinks this research marks a major scientific milestone and tool to add to humanitys technological toolbox.

This is very strong evidence that we will one day have this power, and it will be possible [to create synthetic life], Wilson says. Whether we decide to do that or not because of ethics or even the potential upsides thats a question for society at large.

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Scientists have created a mechanical womb that can grow life in the lab - Inverse

The decision will have widespread implications for the cell and gene therapy (CGT) sector as well as for patient safety, says theInternational Society for Cell & Gene Therapy (ISCT).

The judgement is flawed, according to the industry organization. It said the decision has inserted regulatory uncertainty into the CGT market, creating opportunities for clinics offering purported treatments that are scientifically unproven and potentially dangerous to patients:

The ruling reinforces the imperative market need for informative resources that establish scientific consensus, standards, and best practices, commentedISCT president, Jacques Galipeau.

Late August saw a US federal judge, Jesus G Bernal of the Central District of California, issue a landmark decision siding with the California Stem Cell Treatment Center (CSCTC) and Cell Surgical Network Corporation, in a lawsuit brought by the US Food and Drug Administration (FDA).

The FDA took the legal action against CSCTC in 2018 to assert regulatory authority over stem cell therapies. The agencys position is that taking a patients fat and digesting it with an enzyme to isolate the stem cell fraction creates a biologic drug that requires full FDA approval.

The court rejected this argument.Instead, the judge accepted CSCTCs position that its treatments qualified for an exception from FDA regulations, in part because they were tantamount to surgical procedures.

The court wrote: "The adipose tissue the defendants remove from patients clearly consists of human cells. And whatever is injected back into patients as part of [the] defendants' SVF surgical procedure and expanded MSC surgical procedure certainly contains such cells."

Reacting to the decision, Dr Elliott Lander, co-founder of CSCTC, said the centre appreciated the court's clear and unequivocal ruling, which affirms what we have been saying for 12 years: that our innovative surgical approach to personal cell therapy is safe and legal.

However, Professor Paul Knoepfler, whois based at the UC Davis Department of Cell Biology and Human Anatomy, disagrees. He claims the judge wrongly concluded that stromal vascular fraction (SVF) cells are not changed by the procedure to isolate them.

And the ISCT also believes that scientific inaccuracies in the ruling may have impacted the judges decision.

Its committee on the ethics of cell and gene therapy identified several examples of statements that are problematic and unfounded:

Firstly, they found that the ruling made several statements concerning SVF that are both inaccurate and unsupported by current scientific knowledge. "The ruling mistakenly claims the production of SVF is essentially equivalent to surgery and mischaracterizes SVF as a naturally occurring, circulating, unaltered biological entity that is simply relocated from adipose tissue to other diseased parts of the body by surgical means."

Secondly, the committee argues that the court's assertion that the clinical networks use FDA-authorized devices to produce autologous stem cell-based interventions does not consider that the devices in question may not have been authorized by the FDA, or authorized for other purposes, and have not been designed to produce stem cell therapies.

They also found that the statement that culture-expanded mesenchymal stem cells (MSCs) should not be regulated as drugs conflicts with scientific evidence. "This statement opens the door to unchecked administration of poorly characterized and non-standardized cell preparations with unknown safety and efficacy and may pose significant risks to patients."

Laertis Ikonomou, chair of the ISCT committee on the CGT ethics, said: "ISCT has worked for many years now, alongside the FDA and other regulators across the globe, to ensure all those offering cell and gene, and advanced therapies, operate within established clinical regulatory frameworks to uphold scientific standards and ensure treatments are safe and effective before they reach patients. CGTs currently hold unparalleled potential to treat a vast range of conditions that are underserved needs. However, as one of the most advanced and novel fields of medicine, enhancing patient's own cells, these therapies must operate entirely through a global regulatory framework subject to the most stringent scientific standards."

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ISCT: California stem cell ruling is flawed and has inserted regulatory uncertainty into the CGT market - BioPharma-Reporter.com

Scientists have created synthetic mouse embryos from stem cells without a dads sperm or a moms egg or womb.

The lab-created embryos mirror a natural mouse up to 8 days after fertilization, containing the same structures, including one like a beating heart.

In the near term, researchers hope to use these so-called embryoids to better understand early stages of development and study mechanisms behind disease without the need for as many lab animals. The feat could also lay the foundation for creating synthetic human embryos for research in the future.

We are undoubtedly facing a new technological revolution, still very inefficient but with enormous potential, said Llus Montoliu, a research professor at the National Biotechnology Centre in Spain who is not part of the research. It is reminiscent of such spectacular scientific advances as the birth of Dolly the sheep and others.

A study published Thursday in the journal Nature, by Magdalena Zernicka-Goetz at the California Institute of Technology and her colleagues, was the latest to describe the synthetic mouse embryos. A similar study, by Jacob Hanna at the Weizmann Institute of Science in Israel and his colleagues, was published earlier this month in the journal Cell. Hanna was also a coauthor on the Nature paper.

Zernicka-Goetz, an expert in stem cell biology, said one reason to study the early stages of development is to get more insight into why the majority of human pregnancies are lost at an early stage and embryos created for in vitro fertilization fail to implant and develop in up to 70% of cases. Studying natural development is difficult for many reasons, she said, including the fact that very few human embryos are donated for research and scientists face ethical constraints.

Building embryo models is an alternative way to study these issues.

To create the synthetic embryos, or embryoids, described in the Nature paper, scientists combined embryonic stem cells and two other types of stem cells all from mice. They did this in the lab, using a particular type of dish that allowed the three types of cells to come together. While the embryoids they created werent all perfect, Zernicka-Goetz said, the best ones were indistinguishable from natural mouse embryos. Besides the heart-like structure, they also develop head-like structures.

This is really the first model that allows you to study brain development in the context of the whole developing mouse embryo, she said.

The roots of this work go back decades, and both Zernicka-Goetz and Hanna said their groups were working on this line of research for many years. Zernicka-Goetz said her group submitted its study to Nature in November.

Scientists said next steps include trying to coax the synthetic mouse embryos to develop past 8 days with the eventual goal of getting them to term, which is 20 days for a mouse.

At this point, they struggle to go past the 8 1/2-day mark, said Gianluca Amadei, a coauthor on the Nature paper based at the University of Cambridge. We think that we will be able to get them over the hump, so to speak, so they can continue developing.

The scientists expect that after about 11 days of development the embryo will fail without a placenta, but they hope researchers can someday also find a way to create a synthetic placenta. At this point, they dont know if they will be able to get the synthetic embryos all the way to term without a mouse womb.

Researchers said they dont see creating human versions of these synthetic embryos soon but do see it happening in time. Hanna called it the next obvious thing.

Other scientists have already used human stem cells to create a blastoid, a structure mimicking a pre-embryo, that can serve as a research alternative to a real one.

Such work is subject to ethical concerns. For decades, a 14-day rule on growing embryos in the lab growing human embryos in the lab has guided researchers. Last year, the International Society for Stem Cell Research recommended relaxing the rule under limited circumstances.

Scientists stress that growing a baby from a synthetic human embryo is neither possible nor under consideration.

Perspective on this report is important since, without it, the headline that a mammalian embryo has been built in vitro can lead to the thought that the same can be done with humans soon, said developmental biologist Alfonso Martinez Arias of the Universitat Pompeu Fabra in Spain, whose group has developed alternative stem cell based models of animal development.

In the future, similar experiments will be done with human cells and that, at some point, will yield similar results, he said. This should encourage considerations of the ethics and societal impact of these experiments before they happen.

(AP)

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Scientists Use Stem Cells to Create Synthetic Mouse Embryos