Adult pancreatic acinar cells give rise to ducts but not endocrine cells in response to growth factor signaling

Abstract

SUMMARYStudies in both humans and rodents have found that insulin + cells appear within or near ducts of the adult pancreas, particularly following damage or disease, suggesting that these insulin + cells arise de novo from ductal epithelium. We have found that insulin + cells are continuous with duct cells in the epithelium that makes up the hyperplastic ducts of both chronic pancreatitis and pancreatic cancer in humans. Therefore, we tested the hypothesis that both hyperplastic ductal cells and their associated insulin + cells arise from the same cell of origin. Using a mouse model that develops insulin + cell-containing hyperplastic ducts in response to the growth factor TGF, we performed genetic lineage tracing experiments to determine which cells gave rise to both hyperplastic ductal cells and duct-associated insulin + cells. We found that hyperplastic ductal cells arose largely from acinar cells that changed their cell fate, or transdifferentiated, into ductal cells. However, insulin + cells adjacent to acinar-derived ductal cells arose from pre-existing insulin + cells, suggesting that islet endocrine cells can intercalate into hyperplastic ducts as they develop. We conclude that apparent pancreatic plasticity can result both from the ability of acinar cells to change fate and of endocrine cells to reorganize in association with duct structures.

Neurogenin3 Activation Is Not Sufficient to Direct Duct-to-Beta Cell Transdifferentiation in the Adult Pancreas

“…Using either this dye-labeling or a Ngn3-Cre labeling system, we found that adult Ngn3-activated duct cells do not give rise to beta cells or other endocrine cells, consistent with a previous report (58). Thus, Ngn3 may not be an ideal marker for the identification of beta cell progenitors in adults.…”

“…However, RIP-Cre-ERT mice (4) were reported to have either prolonged tamoxifen-induced cre activation (59), or pre-labeling of beta cells in young (60) or aged mice (58), as well as cell-type specific apoptosis (61). Other CreERT strains could potentially suffer from similar flaws related to specificity and sensitivity.…”

Progenitor cell domains in the developing and adult pancreas

“…22 Furthermore, work conducted in the Means laboratory has demonstrated that b cells residing in or near ductal structures in the MT-TGFa mouse model arise from pre-existing islets and not from a non-bcell source. 35 Combined, our lineage analyses, as well as studies by others, strongly suggest that ductal cells in the adult mouse in STZ-and vehicle-treated control mice ( Fig. 2A, n = 3 + cells was induced by tamoxifen injection at three weeks of age, and diphtheria toxin was subsequently administered to male mice at eight weeks of age as per the protocol devised by Thorel and colleagues.…”

Pancreas organogenesis: From bud to plexus to gland

“…In principle, the full transdifferentiation potential of the acini and ducts might be revealed only when better, much higher efficiency labeling is achieved with new lineage-tracing tools. When TGF-a over-expression was used to generate duct hyperplasia, lineage-tracing of acinar cells using Elastase-Cre or villinCre suggested that most hyperplastic ducts were transdifferentiated from mature acini, and that any endocrine cells detected in/near these duct structures did not come from acini or hyperplastic duct cells (Blaine et al, 2010). Taken together, these studies have led to the same conclusion that acinar cells can only give rise to acinar and ductal cells, but not endocrine cells, upon injury-induced regeneration.…”