The promise of stem cell-derived islet replacement therapy.
Ontology highlight
ABSTRACT:
SUBMITTER: Melton D
PROVIDER: S-EPMC8012315 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In this Commentary, we echo the conclusions of a recent review titled "The promise of stem cell-derived islet replacement therapy," which highlighted recent advances in producing glucose responsive "islets" from stem cells and the benefits of their use in islet transplant therapy in type 1 diabetes (T1D). The review also outlined the status of clinical islet transplantation and the challenges that have prevented it from reaching its full therapeutic promise. We agree with the conclusions of the review and suggest that the identified challenges may be overcome by using the eye anterior chamber as an islet transplant site. We anticipate that the combination of stem cell-derived islets and intraocular transplant could help this promising T1D therapy reach full fruition.
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Project description:Encapsulation of human embryonic stem-cell-differentiated beta cell clusters (hES-?C) holds great promise for cell replacement therapy for the treatment of diabetics without the need for chronic systemic immune suppression. Here, we demonstrate a nanoporous immunoprotective polymer thin film cell encapsulation device that can exclude immune molecules while allowing exchange of oxygen and nutrients necessary for in vitro and in vivo stem cell viability and function. Biocompatibility studies show the device promotes neovascular formation with limited foreign body response in vivo. The device also successfully prevented teratoma escape into the peritoneal cavity of mice. Long-term animal studies demonstrate evidence of engraftment, viability, and function of cells encapsulated in the device after 6 months. Finally, in vivo study confirms that the device was able to effectively immuno-isolate cells from the host immune system.
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Project description:Insulin injection is currently the main therapy for type 1 diabetes (T1D) or late stage of severe type 2 diabetes (T2D). Human pancreatic islet transplantation confers a significant improvement in glycemic control and prevents life-threatening severe hypoglycemia in T1D patients. However, the shortage of cadaveric human islets limits their therapeutic potential. In addition, chronic immunosuppression, which is required to avoid rejection of transplanted islets, is associated with severe complications, such as an increased risk of malignancies and infections. Thus, there is a significant need for novel approaches to the large-scale generation of functional human islets protected from autoimmune rejection in order to ensure durable graft acceptance without immunosuppression. An important step in addressing this need is to strengthen our understanding of transplant immune tolerance mechanisms for both graft rejection and autoimmune rejection. Engineering of functional human pancreatic islets that can avoid attacks from host immune cells would provide an alternative safe resource for transplantation therapy. Human pluripotent stem cells (hPSCs) offer a potentially limitless supply of cells because of their self-renewal ability and pluripotency. Therefore, studying immune tolerance induction in hPSC-derived human pancreatic islets will directly contribute toward the goal of generating a functional cure for insulin-dependent diabetes. In this review, we will discuss the current progress in the immune protection of stem cell-derived islet cell therapy for treating diabetes.
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Project description:Stem-cell-derived tissues offer platforms to study organ development, model physiology during health and disease, and test novel therapies. We describe methods to isolate cells at successive stages during in vitro differentiation of human stem cells into the pancreatic endocrine lineage. Using flow cytometry, we purify live lineage intermediates in numbers not available by fetal biopsy. These include pancreatic and endocrine progenitors, isolated based on known surface markers. We further report a strategy that leverages intracellular zinc content and DPP4/CD26 expression to separate monohormonal insulin+ β cells from polyhormonal counterparts. These methods enable comprehensive molecular profiling during human islet lineage progression. © 2020 Wiley Periodicals LLC. Basic Protocol: In vitro isolation of human islet developmental intermediates.
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Project description:Remarkable advances in protocol development have been achieved to manufacture insulin-secreting islets from human pluripotent stem cells (hPSCs). Distinct from current approaches, we devised a tunable strategy to generate islet spheroids enriched for major islet cell types by incorporating PDX1+ cell budding morphogenesis into staged differentiation. In this process that appears to mimic normal islet morphogenesis, the differentiating islet spheroids organize with endocrine cells that are intermingled or arranged in a core-mantle architecture, accompanied with functional heterogeneity. Through in vitro modelling of human pancreas development, we illustrate the importance of PDX1 and the requirement for EphB3/4 signaling in eliciting cell budding morphogenesis. Using this new approach, we model Mitchell-Riley syndrome with RFX6 knockout hPSCs illustrating unexpected morphogenesis defects in the differentiation towards islet cells. The tunable differentiation system and stem cell-derived islet models described in this work may facilitate addressing fundamental questions in islet biology and probing human pancreas diseases.
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Project description:Stem cell therapies are being explored for the treatment of various diseases, including haematological disease, immune disease, neurodegenerative disease, and tissue injuries. Alternatively, stem cell-derived exosomes may provide similar clinical benefits without the biosafety concerns associated with the transplantation of living cells. However, large-scale manufacturing and purification, batch-to-batch variation, and analysis of the complex cargos of exosomes will need to be addressed to enable their clinical translation.
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Project description:Stem cell-derived β cells offer an alternative to primary islets for biomedical discoveries as well as a potential surrogate for islet transplantation. The expense and challenge of obtaining and maintaining functional stem cell-derived β cells calls for a need to develop better high-content and high-throughput culture systems. Microphysiological systems (MPS) are promising high-content in vitro platforms, but scaling for high-throughput screening and discoveries remain a challenge. Traditionally, simultaneous multiplexing of liquid handling and cell loading poses a challenge in the design of high-throughput MPS. Furthermore, although MPS for islet β culture/testing have been developed, studies on multi-day culture of stem-cell derived β cells in MPS have been limited. We present a scalable, multiplexed islet β MPS device that incorporates microfluidic gradient generators to parallelize fluid handling for culture and test conditions. We demonstrated the viability and functionality of the stem cell-derived enriched β clusters (eBCs) for a week, as assessed by the ∼2 fold insulin release by the clusters to glucose challenge. To show the scalable multiplexing for drug testing, we demonstrated the loss of stimulation index after long-term exposure to logarithmic concentration range of glybenclamide. The MPS cultured eBCs also confirmed a glycolytic bottleneck as inferred by insulin secretion responses to metabolites methyl succinate and glyceric acid. Thus, we present an innovative culture platform for eBCs with a balance of high-content and high-throughput characteristics.
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Project description:Dendritic cell (DC)-based vaccines designed to target cancer stem cells (CSC) can induce significant antitumor responses via conferring host anti-CSC immunity. Our recent studies have demonstrated that CSC-DC vaccine could inhibit metastasis of primary tumors and induce humoral immune responses against cancer stem cells. This approach highlights the promise of cancer stem cell vaccine in cancer immunotherapy.
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Project description:Glaucoma, characterized by a degenerative loss of retinal ganglion cells, is the second leading cause of blindness worldwide. There is currently no cure for vision loss in glaucoma because retinal ganglion cells do not regenerate and are not replaced after injury. Human stem cell-derived retinal ganglion cell transplant is a potential therapeutic strategy for retinal ganglion cell degenerative diseases. In this review, we first discuss a 2D protocol for retinal ganglion cell differentiation from human stem cell culture, including a rapid protocol that can generate retinal ganglion cells in less than two weeks and focus on their transplantation outcomes. Next, we discuss using 3D retinal organoids for retinal ganglion cell transplantation, comparing cell suspensions and clusters. This review provides insight into current knowledge on human stem cell-derived retinal ganglion cell differentiation and transplantation, with an impact on the field of regenerative medicine and especially retinal ganglion cell degenerative diseases such as glaucoma and other optic neuropathies.
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Project description:In the absence of effective endogenous repair mechanisms after cardiac injury, cell-based therapies have rapidly emerged as a potential novel therapeutic approach in ischaemic heart disease. After the initial characterization of putative endothelial progenitor cells and their potential to promote cardiac neovascularization and to attenuate ischaemic injury, a decade of intense research has examined several novel approaches to promote cardiac repair in adult life. A variety of adult stem and progenitor cells from different sources have been examined for their potential to promote cardiac repair and regeneration. Although early, small-scale clinical studies underscored the potential effects of cell-based therapy largely by using bone marrow (BM)-derived cells, subsequent randomized-controlled trials have revealed mixed results that might relate, at least in part, to differences in study design and techniques, e.g. differences in patient population, cell sources and preparation, and endpoint selection. Recent meta-analyses have supported the notion that administration of BM-derived cells may improve cardiac function on top of standard therapy. At this stage, further optimization of cell-based therapy is urgently needed, and finally, large-scale clinical trials are required to eventually proof its clinical efficacy with respect to outcomes, i.e. morbidity and mortality. Despite all promises, pending uncertainties and practical limitations attenuate the therapeutic use of stem/progenitor cells for ischaemic heart disease. To advance the field forward, several important aspects need to be addressed in carefully designed studies: comparative studies may allow to discriminate superior cell populations, timing, dosing, priming of cells, and delivery mode for different applications. In order to predict benefit, influencing factors need to be identified with the aim to focus resources and efforts. Local retention and fate of cells in the therapeutic target zone must be improved. Further understanding of regenerative mechanisms will enable optimization at all levels. In this context, cell priming, bionanotechnology, and tissue engineering are emerging tools and may merge into a combined biological approach of ischaemic tissue repair.
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