Recent progress in generation of human surrogate β cells.

PURPOSE OF REVIEW: This review evaluates recent progress in several approaches aimed at developing human surrogate β cells, and identifies gaps that need to be filled for bringing them closer to clinical application. RECENT
FINDINGS: Cells expanded in vitro from human cadaver donor β cells under conditions causing dedifferentiation have been shown to undergo redifferentiation following inhibition of the Notch pathway. Efforts for differentiation of insulin-producing cells from human pluripotent stem cells have focused on isolation and expansion of intermediate-stage cells. The role of mesenchyme in expansion of pancreas progenitors has been emphasized by mouse cell ablation, and co-culture of human embryonic stem cell-derived definitive endoderm with mesenchyme. Incomplete removal of Polycomb-mediated repression of endocrine genes in embryonic stem cell-derived insulin-producing cells generated in vitro has been suggested to be responsible for their immature phenotype. Induced pluripotent stem cells reprogrammed from β cells have been shown to exhibit an enhanced differentiation capacity toward insulin-producing cells, compared with other pluripotent stem cells. A new approach for reprogramming non-β into β-like cells involving transcription factor gene ablation has been demonstrated in mouse enteroendocrine cells in vivo.
SUMMARY: New insights into the stumbling blocks in expansion of human donor islet cells, differentiation of pluripotent stem cells, and reprogramming of non-β cell types are shaping improved strategies, which are likely to bring us closer to the goal of generating abundant human surrogate β cells.