Mitigating Ischemic Injury of Stem Cell-Derived Insulin-Producing Cells after Transplant

Abstract

SummaryThe advent of large-scale in vitro differentiation of human stem cell-derived insulin-producing cells (SCIPC) has brought us closer to treating diabetes using stem cell technology. However, decades of experiences from islet transplantation show that ischemia-induced islet cell death after transplant severely limits the efficacy of the therapy. It is unclear to what extent human SCIPC are susceptible to ischemia. In this study, we show that more than half of SCIPC die shortly after transplantation. Nutrient deprivation and hypoxia acted synergistically to kill SCIPC in vitro. Amino acid supplementation rescued SCIPC from nutrient deprivation, likely by providing cellular energy. Generating SCIPC under physiological oxygen tension of 5% conferred hypoxia resistance without affecting their differentiation or function. A two-pronged strategy of physiological oxygen acclimatization during differentiation and amino acid supplementation during transplantation significantly improved SCIPC survival after transplant.

Insulin mutations impair beta-cell development in a patient-derived iPSC model of neonatal diabetes

“…Therefore, a small percentage of the cells could have differentiated into alternative cell identities although our results indicate that impaired proliferation and growth is likely to be the main cause for the demise of the INS mutant cells. A potential limitation in the analysis of grafted cells is the extensive ischemia induced cell death upon transplantation (Faleo et al, 2017), which could skew cell type proportions and increase graft to graft variability.…”

Supporting Survival of Transplanted Stem‐Cell‐Derived Insulin‐Producing Cells in an Encapsulation Device Augmented with Controlled Release of Amino Acids

“…[16–18] We have shown previously that hypoxia and nutrient deprivation, consequences of ischemia, synergistically kill stem cell-derived insulin-producing cells. Moreover, supplementation of single amino acid, particularly alanine and glutamine, effectively rescued beta cells from nutrient deprivation [19] Therefore, in this study, we present an improvement in the encapsulation device by fabricating a compartment that releases amino acids within the encapsulation device to sustain graft viability after transplant.…”

Practical ways to achieve targets in diabetes care conference

“…Specifically, Dr Sussel stated that the field is focused on induced pluripotent stem cells (iPSCs) within an encapsulation system. Though this therapy does not have the same barriers as transdifferentiation of non‐beta cells and human islet transplantations (ie, unsuccessful attempts to reprogram human non‐beta cells into beta cells and insufficient beta cell numbers for islet transplantation), iPSCs can lose viability quickly due to insufficient vascularization and oxygen delivery, but the addition of alanine and glutamine may mitigate this . Encapsulation systems might be utilized in protecting these cells against immune rejection.…”