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.

3D Bioprinting of Multicellular Stem Cell‐Derived Constructs to Model Pancreatic Cell Differentiation

“…In addition, quantification of anti‐Ki67 antibody labeling revealed that 30% of the cells in the bioprinted construct were still in the active phase of the cell cycle 12 days after printing (Figure 2H). This observation is in line with the proliferation rate of human pluripotent stem cells that were differentiated into pancreatic progenitors and have been found to contain the replication marker Ki67 at 30%–50% (reviewed in reference [ 50 ] ).…”

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.…”