In the past decade, new approaches have been explored that are aimed at restoring functional β cell mass as a treatment strategy for diabetes. The two most intensely pursued strategies are β cell replacement through conversion of other cell types and β cell regeneration by enhancement of β cell replication. The approach closest to clinical implementation is the replacement of β cells with human pluripotent stem cell–derived (hPSC-derived) cells, which are currently under investigation in a clinical trial to assess their safety in humans. In addition, there has been success in reprogramming developmentally related cell types into β cells. Reprogramming approaches could find therapeutic applications by inducing β cell conversion in vivo or by reprogramming cells ex vivo followed by implantation. Finally, recent studies have revealed novel pharmacologic targets for stimulating β cell replication. Manipulating these targets or the pathways they regulate could be a strategy for promoting the expansion of residual β cells in diabetic patients. Here, we provide an overview of progress made toward β cell replacement and regeneration and discuss promises and challenges for clinical implementation of these strategies.
Jacqueline R. Benthuysen, Andrea C. Carrano, Maike Sander
β cell replacement from human pluripotent stem cell sources.
Currently pursued approaches include implantation of in vitro–generated pancreatic progenitor cells or β-like cells. In vitro–produced pancreatic progenitor cells differentiate into β cells within 16 weeks after implantation. Cell delivery in an encapsulation device prevents immune cells from contacting implanted cells derived from human embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs), while allowing free exchange of nutrients and hormones, including oxygen, glucose, and insulin. Precursors to β cells are depicted in yellow and insulin-producing cells in green.