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.

Stem Cell-Derived β Cells: A Versatile Research Platform to Interrogate the Genetic Basis of β Cell Dysfunction

“…On the other hand, modeling adaptive proliferation of adult β cells with SC-β has potential advantages but also some weaknesses that should be addressed. Basal proliferation of SC-β is usually defined as “low” but is still much higher than that of native adult human β cells (1% vs. 0.2–0.5%) [ 331 , 332 ]. It is possible that future improvements in differentiation protocols will enhance SC-β maturity bringing the proliferation rate close to that of adult β cells.…”

Islet Biology During COVID-19: Progress and Perspectives

“…Using b-cell lines and mice, Ansarullah et al showed that inceptor interacts with the receptors for insulin and insulin growth factor 1 to promote their internalization via clathrin-mediated endocytosis, protecting b cells from autocrine/paracrine stimulation by their own insulin (14). Knockout of the inceptor gene in mice enhances b-cell proliferation and mass-a critical finding that could help to increase bcell numbers for diabetes therapy (15). In addition, if inceptor is found in other insulin-sensitive tissues, blocking it could facilitate a reversal of insulin resistance.…”