Harnessing Proliferation for the Expansion of Stem Cell-Derived Pancreatic Cells: Advantages and Limitations

Abstract

Restoring the number of glucose-responsive β-cells in patients living with diabetes is critical for achieving normoglycemia since functional β-cells are lost during the progression of both type 1 and 2 diabetes. Stem cell-derived β-cell replacement therapies offer an unprecedented opportunity to replace the lost β-cell mass, yet differentiation efficiencies and the final yield of insulin-expressing β-like cells are low when using established protocols. Driving cellular proliferation at targeted points during stem cell-derived pancreatic progenitor to β-like cell differentiation can serve as unique means to expand the final cell therapeutic product needed to restore insulin levels. Numerous studies have examined the effects of β-cell replication upon functionality, using primary islets in vitro and mouse models in vivo, yet studies that focus on proliferation in stem cell-derived pancreatic models are only just emerging in the field. This mini review will discuss the current literature on cell proliferation in pancreatic cells, with a focus on the proliferative state of stem cell-derived pancreatic progenitors and β-like cells during their differentiation and maturation. The benefits of inducing proliferation to increase the final number of β-like cells will be compared against limitations associated with driving replication, such as the blunted capacity of proliferating β-like cells to maintain optimal β-cell function. Potential strategies that may bypass the challenges induced by the up-regulation of cell cycle-associated factors during β-cell differentiation will be proposed.

Keywords: beta cell; diabetes; human pluripotent stem cell; in vitro differentiation; islet; proliferation.

Figure 1

Reported mechanisms and caveats for expanding cells during β-like cell differentiation. Previously reported methods for inducing replication of human pluripotent stem cells (hPSC) to end-stage β-like cells demonstrated that hPSC, definitive endoderm (DE), foregut (FG), and pancreatic progenitor (PP) stages are able to undergo significant expansion with the development of optimized culture conditions (indicated with check mark). These expanded cells are able to maintain their developmental potential with serial passaging. Although proliferation rates have been reported for endocrine progenitors (EP), methods to induce their replication in vitro are not well-studied (indicated with question mark). Inducing replication in β-like cells has been successfully initiated. However, β-like cells were only examined after a limited period of expansion in vitro (indicated by L), and the long-term effects of driving proliferation are not known. This figure was created using BioRender.com.