Advances in Islet Transplantation and the Future of Stem Cell-Derived Islets to Treat Diabetes.

β-Cell replacement for type 1 diabetes (T1D) can restore normal glucose homeostasis, thereby eliminating the need for exogenous insulin and halting the progression of diabetes complications. Success in achieving insulin independence following transplantation of cadaveric islets fueled academic and industry efforts to develop techniques to mass produce β cells from human pluripotent stem cells, and these have now been clinically validated as an alternative source of regulated insulin production. Various encapsulation strategies are being pursued to contain implanted cells in a retrievable format, and different implant sites are being explored with some strategies reaching clinical studies. Stem cell lines, whether derived from embryonic sources or reprogrammed somatic cells, are being genetically modified for designer features, including immune evasiveness to enable implant without the use of chronic immunosuppression. Although hurdles remain in optimizing large-scale manufacturing, demonstrating efficacy, durability, and safety, products containing stem cell-derived β cells promise to provide a potent treatment for insulin-dependent diabetes.

Kieffer TJ ，Hoesli CA ，Shapiro AMJ 《Cold Spring Harbor Perspectives in Medicine》

Stem Cell-Based Clinical Trials for Diabetes Mellitus.

Since its introduction more than twenty years ago, intraportal allogeneic cadaveric islet transplantation has been shown to be a promising therapy for patients with Type I Diabetes (T1D). Despite its positive outcome, the impact of islet transplantation has been limited due to a number of confounding issues, including the limited availability of cadaveric islets, the typically lifelong dependence of immunosuppressive drugs, and the lack of coverage of transplant costs by health insurance companies in some countries. Despite improvements in the immunosuppressive regimen, the number of required islets remains high, with two or more donors per patient often needed. Insulin independence is typically achieved upon islet transplantation, but on average just 25% of patients do not require exogenous insulin injections five years after. For these reasons, implementation of islet transplantation has been restricted almost exclusively to patients with brittle T1D who cannot avoid hypoglycemic events despite optimized insulin therapy. To improve C-peptide levels in patients with both T1 and T2 Diabetes, numerous clinical trials have explored the efficacy of mesenchymal stem cells (MSCs), both as supporting cells to protect existing β cells, and as source for newly generated β cells. Transplantation of MSCs is found to be effective for T2D patients, but its efficacy in T1D is controversial, as the ability of MSCs to differentiate into functional β cells in vitro is poor, and transdifferentiation in vivo does not seem to occur. Instead, to address limitations related to supply, human embryonic stem cell (hESC)-derived β cells are being explored as surrogates for cadaveric islets. Transplantation of allogeneic hESC-derived insulin-producing organoids has recently entered Phase I and Phase II clinical trials. Stem cell replacement therapies overcome the barrier of finite availability, but they still face immune rejection. Immune protective strategies, including coupling hESC-derived insulin-producing organoids with macroencapsulation devices and microencapsulation technologies, are being tested to balance the necessity of immune protection with the need for vascularization. Here, we compare the diverse human stem cell approaches and outcomes of recently completed and ongoing clinical trials, and discuss innovative strategies developed to overcome the most significant challenges remaining for transplanting stem cell-derived β cells.

de Klerk E ，Hebrok M 《Frontiers in Endocrinology》

Human Induced Pluripotent Stem Cells in the Curative Treatment of Diabetes and Potential Impediments Ahead.

Dadheech N ，James Shapiro AM 《Advances in Experimental Medicine and Biology》

The future treatment for type 1 diabetes: Pig islet- or stem cell-derived β cells?

Replacement of β cells is only a curative approach for type 1 diabetes (T1D) patients to avoid the threat of iatrogenic hypoglycemia. In this pursuit, islet allotransplantation under Edmonton's protocol emerged as a medical miracle to attain hypoglycemia-free insulin independence in T1D. Shortage of allo-islet donors and post-transplantation (post-tx) islet loss are still unmet hurdles for the widespread application of this therapeutic regimen. The long-term survival and effective insulin independence in preclinical studies have strongly suggested pig islets to cure overt hyperglycemia. Importantly, CRISPR-Cas9 technology is pursuing to develop "humanized" pig islets that could overcome the lifelong immunosuppression drug regimen. Lately, induced pluripotent stem cell (iPSC)-derived β cell approaches are also gaining momentum and may hold promise to yield a significant supply of insulin-producing cells. Theoretically, personalized β cells derived from a patient's iPSCs is one exciting approach, but β cell-specific immunity in T1D recipients would still be a challenge. In this context, encapsulation studies on both pig islet as well as iPSC-β cells were found promising and rendered long-term survival in mice. Oxygen tension and blood vessel growth within the capsules are a few of the hurdles that need to be addressed. In conclusion, challenges associated with both procedures, xenotransplantation (of pig-derived islets) and stem cell transplantation, are required to be cautiously resolved before their clinical application.

Naqvi RA ，Naqvi AR ，Singh A ，Priyadarshini M ，Balamurugan AN ，Layden BT ... -  《Frontiers in Endocrinology》

Lessons from Human Islet Transplantation Inform Stem Cell-Based Approaches in the Treatment of Diabetes.

Diabetes mellitus is characterized by the body's inability to control blood glucose levels within a physiological range due to loss and/or dysfunction of insulin producing beta cells. Progressive beta cell loss leads to hyperglycemia and if untreated can lead to severe complications and/or death. Treatments at this time are limited to pharmacologic therapies, including exogenous insulin or oral/injectable agents that improve insulin sensitivity or augment endogenous insulin secretion. Cell transplantation can restore physiologic endogenous insulin production and minimize hyper- and hypoglycemic excursions. Islet isolation procedures and management of transplant recipients have advanced over the last several decades; both tight glycemic control and insulin independence are achievable. Research has been conducted in isolating islets, monitoring islet function, and mitigating the immune response. However, this procedure is still only performed in a small minority of patients. One major barrier is the scarcity of human pancreatic islet donors, variation in donor pancreas quality, and variability in islet isolation success. Advances have been made in generation of glucose responsive human stem cell derived beta cells (sBCs) and islets from human pluripotent stem cells using directed differentiation. This is an emerging promising treatment for patients with diabetes because they could potentially serve as an unlimited source of functional, glucose-responsive beta cells. Challenges exist in their generation including long term survival of grafts, safety of transplantation, and protection from the immune response. This review focuses on the progress made in islet allo- and auto transplantation and how these advances may be extrapolated to the sBC context.

Triolo TM ，Bellin MD 《Frontiers in Endocrinology》