Report of the Key Opinion Leaders Meeting on Stem Cell-derived Beta Cells

Abstract

Beta cell replacement has the potential to restore euglycemia in patients with insulin-dependent diabetes. Although great progress has been made in establishing allogeneic islet transplantation from deceased donors as the standard of care for those with the most labile diabetes, it is also clear that the deceased donor organ supply cannot possibly treat all those who could benefit from restoration of a normal beta cell mass, especially if immunosuppression were not required. Against this background, the International Pancreas and Islet Transplant Association in collaboration with the Harvard Stem Cell Institute, the Juvenile Diabetes Research Foundation (JDRF), and the Helmsley Foundation held a 2-day Key Opinion Leaders Meeting in Boston in 2016 to bring together experts in generating and transplanting beta cells derived from stem cells. The following summary highlights current technology, recent significant breakthroughs, unmet needs and roadblocks to stem cell-derived beta cell therapies, with the aim of spurring future preclinical collaborative investigations and progress toward the clinical application of stem cell-derived beta cells.

Advances in β-cell replacement therapy for the treatment of type 1 diabetes

“…7 The differentiation of human stem cells to insulin-producing islets provides another potentially unlimited cell source for islet transplantation. 78 Stem cells from human embryos can be differentiated in vitro to a pancreatic endoderm progenitor stage, which, following transplantation in mouse models, further differentiates in vivo into insulin-producing islet tissue that is capable of reversing diabetes. 79,80 However, off-target differentiation of pancreatic ductal structures has been observed with longer-term follow-up of mice that have received transplants.…”

Nanotechnology in cell replacement therapies for type 1 diabetes

“…Immune cell migration through an immunoisolating membrane can threaten graft function. Additionally, escape of cells with pluripotent characteristics which avoided full differentiation into β-cells and have the potential to generate tumors [236,237], poses a significant safety concern [10]. Thus, membranes that prevent cell penetration can dually facilitate graft performance and provide safety to the recipient in stem cell-derived insulin producing cell transplant schemes.…”

“…Despite remarkable advances and reduced patient burden achieved by this device, glucose control still requires patient interaction. β-cell replacement therapies, where primary animal [8] or human [9] islets or stem cell-derived islet-like clusters [10] are transplanted into diabetic patients to replace those destroyed by autoimmune attack, have the potential to provide long-term, stress-free euglycemia restoration.…”

In vivo Environment Swiftly Restricts Human Pancreatic Progenitors Toward Mono-Hormonal Identity via a HNF1A/HNF4A Mechanism

“…Loss of insulin-producing pancreatic β-cells ultimately characterize most diabetic conditions, prompting extensive efforts aimed at replenishing these cells from either endogenous (Chera and Herrera, 2016;Zhou and Melton, 2018) or exogenous sources (Balboa and Otonkoski, 2015). As part of the latter strategies, the employment of human induced pluripotent stem cells (hiPSC) as a source for insulin-producing cells has gained a lot of momentum in the recent years (Loo et al, 2018;Odorico et al, 2018). These methods are based on a stepwise hiPSC differentiation strategy mirroring the stages characterizing β-cells fate acquisition during development (Pagliuca and Melton, 2013;Melton, 2016;Petersen et al, 2018).…”