Reawakening the Duct Cell Progenitor?

Abstract

The generation of new -cells from progenitors is an area of immense research interest in diabetes, given the potential not only for therapeutic -cell replacement by transplantation but also regeneration of endogenous -cells. Defining the progenitors that serve as sources of new -cells in vivo has been an area of considerable debate and research effort (1, 2). Replication of existing -cells has been shown to be an important source of new -cells in rodents throughout life, in health and in response to injury (3). Evidence for transdifferentiation of non-cells, including -cells (4) and pancreatic acinar cells (5, 6) has also emerged in rodents. Most studies have employed models of -cell regeneration after severe -cell loss or pancreatic injury, potentially inducing “facultative” stem cell differentiation, leaving questions as to the importance of these putative progenitors in a physiological context. Pancreatic ductal cells have perhaps received the most interest and study as a potential -cell progenitor. Lineage tracing studies in mice in which carbonic anhydrase-expressing (and therefore likely ductal) cells were marked, provided persuasive evidence that ductal cells can differentiate into -cells in mice after ductal ligation (7), but limitations to such studies, such as the fidelity of the carbonic anhydrase promoter, raised questions that have lingered for a number of years. Although numerous histological studies have shown islets in close association with ducts, and are suggestive that new islets originate from ducts (8) and in response to -cell loss, there have been near as many reports that do not support the idea that ductal cells can give rise to -cells in adult mice (9, 10). An innovative whole-mount imaging approach with 3-dimensional reconstruction employed by El-Gohary et al in this issue of Endocrinology (11) sheds new light on this debate and provides compelling evidence that, at least under certain conditions, pancreatic duct cells can give rise to -cells postnatally. Using whole-mount immunostaining, small ducts were found to reside within the islets, and moreover these intraislet ducts appear to arise from larger pancreatic ducts outside of the islet. Importantly, wholemount imaging of a limited number of young human pancreas samples demonstrated the presence of intraislet ducts in humans as well. The presence of these intraislet ducts was highly age dependent in both mice and humans, peaking in mice at about 5 weeks of age, and being most prevalent in 1-2 month-old human sample. Notably these are times when -cell genesis is high. Somewhat surprisingly, -cell regeneration induced after partial pancreatectomy did not increase the number of intraislet ducts, at least in older (10-wk-old) mice. Building on their earlier finding that TGF may inhibit -cell neogenesis (12), the authors performed partial pancreatectomy in transgenic mice in which TGF signaling is suppressed by constitutive expression of a dominant negative TGF -type II receptor. This transgenic mouse model phenocopied the young mouse with extensive intraislet ducts and allowed El-Gohary et al to carry out lineage tracing to provide further support for their assertion that -cells can arise from ductal cells. For these studies, the pancreatic ductal tree of a Cre-reporter mouse line was infused with an adeno-associated virus serotype 6 virus expressing Cre recombinase under control of the “ductal” Sox9 promoter. After partial pancreatectomy, insulinpositive cells were observed to be lineage labeled, supporting their conclusion that -cells can be derived by neogenesis from pancreatic ductal cells.