Identification and functional analysis of a candidate stem cell population in the adult mouse pancreas
Cell Biology
Final Report Abstract
The presence of progenitor or stem cells in the adult pancreas and their potential involvement in homeostasis and cancer development remain important issues. We showed that mouse centroacinar cells can be identified and isolated by virtue of the mitochondrial enzyme Aldh1b1 that they uniquely express. These cells are necessary and sufficient for the formation of self-renewing adult pancreatic organoids in an Aldh1b1-dependent manner. Aldh1b1-expressing centroacinar cells, are largely quiescent, self-renew and, as shown by genetic lineage tracing, contribute to all three pancreatic lineages in the adult organ under homeostatic conditions. Single cell RNA sequencing analysis of these cells identified a novel progenitor cell population, established its molecular signature and determined distinct differentiation pathways to early progenitors. A distinct feature of these progenitor cells is the preferential expression of small GTPases, including Kras, suggesting that they might be susceptible to Kras driven oncogenic transformation. This finding and the overexpression of Aldh1b1 in human and mouse pancreatic cancers, driven by activated Kras, prompted us to examine the involvement of Aldh1b1 in oncogenesis. We demonstrated genetically that ablation of Aldh1b1 completely abrogates tumor development in a mouse model of KrasG12D- induced pancreatic cancer. We did not anticipate that this work would implicate Aldh1b1 and Aldh1b1 expressing cells in PDAC development. To further address these findings, we generated two new mouse alleles. One enabling expression of CreERT2 from the Aldh1b1 locus while inactivating the endogenous gene, and one setting the induction of Kras* expression under the control of two distinct drivers, enabling its induction specifically in pancreas cells. Preliminary results suggest that, indeed, this leads to precancerous lesions which in the presence of acute pancreatitis in accelerated and results in early PDAC.
Publications
- Aldh1b1 expression defines progenitor cells in the adult pancreas and is required for Kras induced pancreatic cancer (2019). PNAS, 116 (41) 20679-20688
E. Mameishvili, I. Serafimidis, S. Iwaszkiewicz, M. Lesche, S. Reinhardt, N. Bölicke, M. Büttner, D. Stellas, A. Papadimitropoulou, M. Szabolcs, K. Anastassiadis, A. Dahl, F. Theis, A. Efstratiadis and A. Gavalas
(See online at https://doi.org/10.1073/pnas.1901075116) - Proliferation Versus Progenitor Differentiation and Transdifferentiation in Restoring Beta Cell Mass (2021). 12, e722250
E. Spears, I. Serafimidis, A. C. Powers, and A. Gavalas
(See online at https://doi.org/10.3389/fendo.2021.722250)
