The Human Endocrine Pancreas: New Insights on Replacement and Regeneration

Islet transplantation is an effective cell therapy for type 1 diabetes (T1D) but its clinical application is limited due to shortage of donors. After a decade-long period of exploration of potential alternative cell sources, the field has only recently zeroed in on two of them as the most likely to replace islets. These are pluripotent stem cells (PSCs) (through directed differentiation) and pancreatic non-endocrine cells (through directed differentiation or reprogramming). Here we review progress in both areas, including the initiation of Phase I/II clinical trials using human embryonic stem cell (hESc)-derived progenitors, advances in hESc differentiation in vitro, novel insights on the developmental plasticity of the pancreas, and groundbreaking new approaches to induce β cell conversion from the non-endocrine compartment without genetic manipulation.

TrendsStem cell therapies are finally coming of age in the context of pancreatic endocrine regeneration for diabetes. Clinical trials aimed at testing the safety and efficacy of human embryonic stem cell-derived islet surrogates are already ongoing.If successful, these approaches are expected to lead to the phasing out of the use of cadaveric islets for transplantation, exponentially extending our ability to treat millions of type 1 diabetes – and potentially also type 2 diabetes – patients.Different cell populations within the pancreas can regenerate the endocrine compartment through reprogramming, replication, or stimulation of resident progenitors.The field has recently advanced to the point where these phenomena can be induced without the need for genetic manipulation, getting us closer to the design of viable clinical trials for β cell replenishment or endogenous regeneration.