Abstract
Multipotent epithelial cells with high Aldehyde dehydrogenase activity have been previously reported to exist in the adult pancreas. However, whether they represent true progenitor cells remains controversial. In this study, we isolated and characterized cells with ALDH activity in the adult mouse or human pancreas during physiological conditions or injury. We found that cells with ALDH activity are abundant in the mouse pancreas during early postnatal growth, pregnancy, and in mouse models of pancreatitis and type 1 diabetes (T1D). Importantly, a similar population of cells is found abundantly in healthy children, or in patients with pancreatitis or T1D. We further demonstrate that cells with ALDH activity can commit to either endocrine or acinar lineages, and can be divided into four sub-populations based on CD90 and Ecadherin expression. Finally, our in vitro and in vivo studies show that the progeny of ALDH1+/CD90−/Ecad− cells residing in the adult mouse pancreas have the ability to initiate Pancreatic and duodenal homeobox (Pdx1) expression for the first time. In summary, we provide evidence for the existence of a sortable population of multipotent non-epithelial cells in the adult pancreas that can commit to the pancreatic lineage following proliferation and mesenchymal to epithelial transition (MET).
Highlights
In the adult mouse pancreas, β-cell regeneration under physiological conditions occurs through β-cell self-duplication[4,5], and considerable effort has been put into finding ways to stimulate endogenous β-cell proliferation[6]
This protocol provided us with a starting pool of approximately 7 × 106 cells per pancreas highly enriched for viable Dolichos biflorus agglutinin-posiitve (DBA) duct cells (Ecadherin+/DBA+) (Supplementary Fig. 1A)
Quantitative RTPCR analyses confirmed the lack of acinar or β-cell contamination, as no insulin or amylase transcript could be detected in the sorted Aldefluor+ cell pool (Supplementary Fig. 1C)
Summary
In the adult mouse pancreas, β-cell regeneration under physiological conditions occurs through β-cell self-duplication[4,5], and considerable effort has been put into finding ways to stimulate endogenous β-cell proliferation[6]. Recent reports using pancreatic ducts to generate acinar or endocrine cells have focused the search for progenitor cells to within or in proximity to ductal structures[14,15,16]. We have identified a novel population of multipotent Aldefluor+/CD90−/Ecad− mesenchymal cells residing within the adult pancreas that appears to not be derived from the PDX1+ lineage. These cells proliferate during post-natal growth, pregnancy, and in pathological conditions such as pancreatitis and diabetes. These Aldefluor+/CD90−/Ecad− cells undergo a subsequent mesenchymal to epithelial transition prior to committing to a pancreatic lineage by expressing Pdx[1] for the first time
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