Adult tissue sources for new β cells

Abstract

The diabetes pandemic incurs extraordinary public health and financial costs that are projected to expand for the foreseeable future. Consequently, the development of definitive therapies for diabetes is a priority. Currently, a wide spectrum of therapeutic strategies-from implantable insulin delivery devices to transplantation-based cell replacement therapy, to β-cell regeneration-focus on replacing the lost insulin-producing capacity of individuals with diabetes. Among these, β-cell regeneration remains promising but heretofore unproved. Indeed, recent experimental work has uncovered surprising biology that underscores the potential therapeutic benefit of β-cell regeneration. These studies have elucidated a variety of sources for the endogenous production of new β cells from existing cells. First, β cells, long thought to be postmitotic, have demonstrated the potential for regenerative capacity. Second, the presence of pancreatic facultative endocrine progenitor cells has been established. Third, the malleability of cellular identity has availed the possibility of generating β cells from other differentiated cell types. Here, we review the exciting developments surrounding endogenous sources of β-cell production and consider the potential of realizing a regenerative therapy for diabetes from adult tissues.

Figure 1. Theoretical Sources of Insulin

(A) Seven strategies for restoring insulin production. Current research focuses on four methods to restore insulin production through expansion of β-cell mass: 1) directed differentiation of β-cells from human stem cells (hESC or hiPS), 2) transdifferentiation of existing pancreatic cell types to a β-cell fate, 3) generation of new β-cells from existing progenitor cells in the mature pancreas (neogenesis), 4) expansion of β-cell mass from existing β-cell pools (in vitro or in vivo). Three additional strategies may restore insulin production: 5) xenogeneic transplantation, e.g., porcine islets, or 6) allogeneic cadaveric transplantation, and 7) Glucose control devices may be implanted into humans to restore euglycemia. (B) The β-cell differentiation pathway. β-Cell differentiation is directed by the temporally regulated expression of master-regulator transcription factors, shown beneath the arrows. Recapitulation of the normal differentiation pathway is used to direct stem cells toward a β-cell fate. Currently, the full complement of factors required to generate mature, glucose-responsive beta cells from insulin-positive endocrine progenitor cells are unknown.

Figure 2. Potential Sources of New Beta Cells

Three distinct pathways of achieving β-cell mass replenishment have been defined: β-cell expansion, β-cell neogenesis and transdifferentiation of non-β-cells to β-cells. These processes which may occur in-vivo or in-vitro are illustrated within the context of the endocrine and exocrine pancreas. (A) Expansion of pre-existing β-cells may occur directly through beta cell division, or through a mesenchymal cell intermediate produced via an epithelial to mesenchymal transition (EMT). (B) Facultative progenitor cells insulated among non-endocrine epithelial cell populations have the potential to repopulate the endocrine cell population through neogenesis. (C) Pancreatic cells (alpha, duct, and acinar cells), liver cells (hepatocytes and bile ducts), and gut cells (enteroendocrine cells) may be induced to become mature β-cells through a variety of genetic and pharmacologic manipulations.