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March 05, 2015

New clues on how adult pancreas regenerates

Our bodies have a wonderful way to regenerate after injury or illness. In skin cells it was shown that organ-specific adult stem cells are the source of the regeneration, while in liver it is thought that hepatocytes themselves are. Regarding pancreas, there is great debate about whether adult duct cells differentiate into acinar and/or islet cells. The Yoshiya Kawaguchi group at the Dept. of Clinical Application now reports evidence suggesting that adult duct cells have the capacity to differentiate into acinar cells, but not islet cells.
There are three primary factors involved in the differentiation to acinar cells, Sox9, which is present throughout the pancreatic duct but not elsewhere in the pancreas, Notch and Hes1. "Sox9 is very important to keep the identity of duct cells, because it is only expressed there. If Sox9 is reduced, the duct cells lose their identity and differentiate," explains Shinichi Hosokawa, the first author of the study. However, while this is a common theory and has been observed in embryonic cells, no study had demonstrated the relationship of these three elements in the regeneration network for adult pancreas.
To make such an investigation, the team used mice that were designed to have the lower Sox9 expression levels. The duct cells of these mice were seen to differentiate into acinar cells after several days, but found no evidence of differentiation to islet cells. Increasing Notch activity significantly reduced the amount of differentiation while at the same time increasing the amount of Sox9, suggesting the Sox9 effect is dosage dependent. The effects of Hes1, on the other hand, were only detected when it was completely knocked out, suggesting not a dosage effect but a binary one. From these observations, the authors concluded that Notch regulates Sox9 and Hes1 using independent pathways.
 The study thus provides some of the first direct evidence on the plasticity of adult duct cells and the key regulators involved. While insightful, much of the conclusions mirror what has already been observed in embryos. "[The results] are not so surprising. We thought the adult stage and embryonic stage use the same mechanism, but no report proved this," says Hosokawa.
Hosokawa et al. (2015) Impact of Sox9 Dosage and Hes1-mediated Notch Signaling in Controlling the Plasticity of Adult Pancreatic Duct Cells in Mice. Scientific Reports 5:8518.
Published online on February 17, 2015
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