The field has recently advanced to the point where these phenomena can be induced without the need for genetic manipulation, getting us closer to the design of viable clinical trials for β cell replenishment or endogenous regeneration.

Different cell populations within the pancreas can regenerate the endocrine compartment through reprogramming, replication, or stimulation of resident progenitors.

If successful, these approaches are expected to lead to the phasing out of the use of cadaveric islets for transplantation, exponentially extending our ability to treat millions of type 1 diabetes – and potentially also type 2 diabetes – patients.

Stem cell therapies are finally coming of age in the context of pancreatic endocrine regeneration for diabetes. Clinical trials aimed at testing the safety and efficacy of human embryonic stem cell-derived islet surrogates are already ongoing.

Islet transplantation is an effective cell therapy for type 1 diabetes (T1D) but its clinical application is limited due to shortage of donors. After a decade-long period of exploration of potential alternative cell sources, the field has only recently zeroed in on two of them as the most likely to replace islets. These are pluripotent stem cells (PSCs) (through directed differentiation) and pancreatic non-endocrine cells (through directed differentiation or reprogramming). Here we review progress in both areas, including the initiation of Phase I/II clinical trials using human embryonic stem cell (hESc)-derived progenitors, advances in hESc differentiation in vitro, novel insights on the developmental plasticity of the pancreas, and groundbreaking new approaches to induce β cell conversion from the non-endocrine compartment without genetic manipulation.

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Diabetes enhances the proliferation of adult pancreatic multipotent progenitor cells and biases their differentiation to more beta-cell production.

A second pathway for regeneration of adult exocrine and endocrine pancreas. A possible recapitulation of embryonic development.

Impact of Sox9 dosage and Hes1-mediated Notch signaling in controlling the plasticity of adult pancreatic duct cells in mice.

Influence of in vitro and in vivo oxygen modulation on beta cell differentiation from human embryonic stem cells.

Glossary

islet cells that secrete insulin into the bloodstream in a glucose-responsive manner. They are primary targets in autoimmune T1D. β cell demise results in pathological hyperglycemia and lifelong need for exogenous insulin administration. In T2D, peripheral insulin resistance often leads to β cell exhaustion and death. As exogenous insulin is also required in severe T2D cases, strategies for β cell replenishment/regeneration are also potentially applicable.

also known as the non-endocrine pancreatic compartment; comprises >95% of the organ, with the secretion of digestive enzymes as its primary function. This tissue comprises acinar and ductal cells. Acini are connected to the ductal system by centroacinar cells. The ductal tree drains digestive secretions to the duodenum through ducts of increasing caliber.

the archetypical PSCs, obtained from the inner cell mass (ICM) of a human preimplantation embryo (d5–6 blastocyst). These cells are widely considered the gold standard of pluripotency. Embryonic germ (EG) cells are another example of native PSCs.

new PSC types that do not exist in nature, derived by reprogramming differentiated cells. iPScs can theoretically be obtained from any individual. To most practical effects, iPScs and hEScs are functionally equivalent.

also known as the endocrine pancreas, the islets of Langerhans are micro-organ-like cell clusters interspersed within the exocrine pancreas. They maintain glucose homeostasis by secreting specific hormones into the bloodstream. The main islet cell types are α (glucagon secreting), β (insulin secreting), δ (somatostatin secreting), PP (pancreatic polypeptide secreting), and ɛ (ghrelin secreting).

a medical procedure by which islets from a cadaveric pancreas are separated from the non-endocrine fraction and then transplanted. Enzymatic digestion of the organ is followed by gradient separation of the various pancreatic fractions. Isolated islets are implanted in the liver through portal vein catheterization, although current clinical trials are exploring alternative placements such as the omentum (a visceral, highly vascularized fold of the peritoneum). Islet transplantation remains the standard cell therapy for T1D but is limited by the shortage of organs and the necessity for lifelong immunosuppression.

cells with the ability to proliferate indefinitely in vitro under the right conditions while maintaining pluripotency; that is, the capacity to differentiate along all lineages of the three embryonic layers (endoderm, ectoderm, and mesoderm).

non-terminally differentiated cells characterized by a variable degree of potency. Putative progenitor cells within the adult pancreas (PPcs) may be oligopotent (e.g., they would give rise to endocrine cells only) or multipotent (e.g., with multilineage differentiation potential spanning endocrine/exocrine fates).

also called transdifferentiation; refers to a switch in cellular fate that is not brought about by differentiation. It typically refers to experimental methods (chiefly genetic/epigenetic manipulation) inducing the conversion of one cell type into another.