Identification and functional analysis of a candidate stem cell population in the adult mouse pancreas

• Applicant: Professor Dr. Anthony Gavalas, Ph.D.
• Subject Area: Developmental Biology ; Cell Biology
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 385808406

The pancreas is the origin of debilitating and fatal diseases, including diabetes and pancreatic cancer. Thus it is important to understand the homeostatic mechanisms that maintain organ function because their derailment might be at the origin of or significantly contribute to these diseases. Identification of resident pancreatic stem cells could provide fresh insights in the origin of these diseases and suggest new therapeutic venues. However, despite the demonstrated plasticity of the organ under various insults or stimuli, the presence of bona fide adult pancreas stem cells has not been documented.We reasoned that putative adult stem cells may retain expression of embryonic progenitor marker genes, particularly genes that may be involved in metabolic regulation due to the specific metabolic requirements of adult stem cells. Accordingly, we have found that a novel aldehyde dehydrogenase (Aldh) gene, encoding the mitochondrial enzyme Aldh1b1, is expressed in all pancreas progenitors during development and that its expression is retained in the rare centroacinar cells of the adult pancreas. Experimental induction of pancreas regeneration resulted in a large expansion of the number of Aldh1b1+ cells. Preliminary results using a mouse Aldh1b1 lineage tracing line that we generated, showed that adult Aldh1b1+ cells give rise to endocrine, acinar and duct cells acting as bona fide adult pancreas stem cells during homeostasis; something never seen before. These cells can self-renew and expand in vitro for several passages retaining progenitor character. Furthermore, we have isolated a similar population in the human adult pancreas that can also be expanded in culture retaining progenitor character. In this application we propose to document the self-renewal and longevity of the mouse population, its contribution during pancreas homeostasis and after injury and to address the functional significance of Aldh1b1 expression in self-renewal and differentiation of the adult pancreas stem cells in the mouse. To further understand the molecular requirements for self-renewal and differentiation of this population and identify additional specific markers we will perform single cell RNA Seq analysis. Findings will help to better maintain the stem cell character of these cells during in vitro expansion and transplantation experiments will be used to assess their developmental potential following in vitro expansion. These studies aim at a comprehensive analysis of the newly identified candidate adult pancreas stem cells in the mouse and will pave the way for the identification of their human counterparts. The findings will help understand the origins of pancreatic dysfunction and disease and identify possible alternative means to address diabetes and pancreatic cancer.

• DFG Programme: Research Grants