Cellular origins of beta-cell regeneration: a legacy view of historical controversies

Abstract

Beta-cell regeneration represents a major goal of therapy for diabetes. Unravelling the origin of beta cells during pancreatic regeneration could help restore a functional beta-cell mass in diabetes patients. This scientific question has represented a longstanding interest still intensively investigated today. This review focuses on pioneering observations and subsequent theories made 100 years ago and describes how technical innovation helped resolve some, but not all, of the controversies generated by these early investigators. At the end of the 19th century, complete pancreatectomy demonstrated the crucial physiological role of the pancreas and its link with diabetes. Pancreatic injury models, including pancreatectomy and ductal ligation, allowed investigators to describe islet function and to assess the regenerative capacity of the pancreas. Three main theories were proposed to explain the origins of newly formed islets: (i) transdifferentiation of acinar cells into islets, (ii) islet neogenesis, a process reminiscent of islet formation during embryonic development, and (iii) replication of preexisting islet cells. Despite considerable technical innovation in the last 50 years, the origin of new adult beta cells remains highly controversial and the same three theories are still debated today.

Figure 1

Partial pancreatectomy induced β-cell replication in mice at 2 months of age. BrdU was administered for 2 weeks after the procedure prior to sacrifice. Representative pancreatic β-cell histology of pancreas sections immunostained with antibodies against insulin (red) and BrdU (green) and counterstained with DAPI (blue) and photographed with a 40x objective. White arrows indicate insulin and BrdU co-positive cells; Yellow arrows denote BrdU labeled non-insulin containing cells within the islet. Scale bars: 100μm in full image, 20μm within inset. Figure adapted from [101].