Navigating challenges in human pluripotent stem cell-derived islet therapy for type 1 diabetes

Abstract

In the past two decades, several tissues have been generated from the differentiation of human pluripotent stem cells (hPSCs) to model development or disease, and for use in drug testing and cell replacement therapies. A frontliner of hPSC-derived tissues used in cell replacement therapies are the pancreatic cells, which have entered multiple clinical trials since 2014 for the treatment of type 1 diabetes (T1D). Despite challenges in early trials, the detection of endogenous C-peptide in recipients was encouraging. The results and challenges of these trials inspired new areas of research, leading to incremental advances in cell differentiation and delivery technologies, and a deeper understanding of the transplantation microenvironment to enhance therapeutic efficacy and longevity. Reports from the most recent trials demonstrated success in reducing or eliminating exogenous insulin administration for people with T1D, increasing hope for a cure for T1D via regenerative medicine. Recent efforts can be broadly categorized into: (1) improving the cell product as surrogates of native beta cells, (2) promoting engraftment post-transplant to support cell survival, integration into the host, and endocrine function, and (3) developing immunomodulation strategies to reduce or circumvent immunosuppression regimen. In this review, we discuss recent and emerging advances in these three areas and the potential, risk, and scalability of experimental models to the clinic.

Keywords: beta cells; human pluripotent stem cells; immune cells; immunosuppression; islets; transplantation; type 1 diabetes; vascularization.

Figure 1

Schematic showing the summary of signaling pathways targeted to guide the stepwise differentiation of hPSCs to beta cells over the past 20 years (i is inhibition).

Figure 2

Schematic of islet connection to vessels in the native pancreas, versus post-transplantation into the portal vein naked, or the in the subcutis combined with vascularization interventions. (A) in the native pancreas islets are in close contact with the vascular cells, such as endothelial cells and pericytes secrete angiocrine signals and ECM that regulate the islet niche during development, health and disease, and form fenestrated vessels to accommodate rapid exchange of glucose and insulin. (B) A successful method of islet transplantation is via infusion into the portal vein. Initial contact with the host’s blood flow leads to rapid islet death due to instant inflammation. The surviving islets seed into the sinusoids and via this connect can sense glucose and secrete insulin into the bloodstream. (C) Vascularization strategies aim at pre or co-transplantation of vessels with the islets to recreate the islet vascular niche and accommodate endocrine function. Methods such as angiogenic biomaterials, cells and assembled vessels can be successful at various rates.

Figure 3

Strategies to protect SC-islet grafts from immune rejection: (A) Hypoimmunogenic islets can be generated with ablation of HLA expression while maintaining HLA-G and E, and overexpression of PD-L1, or CD47, (B) localized immunomodulation by delivering FasL, IL-10 and TGFβ to the transplantation environment, and (C) physical barriers can be applied to prevent direct contact between immune cells and the transplanted islets.