期刊
DEVELOPMENT
卷 140, 期 4, 页码 751-764出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/dev.090159
关键词
Multipotent pancreas progenitors; Facultative progenitors; Acinar-to-endocrine transdifferentiation; Injury; Mouse; Lineage tracing
资金
- NIH [CA68485, DK20593, DK58404, DK59637]
- Juvenile Diabetes Research Foundation (JDRF)
- National Institutes of Health [U19 DK 042502, U01 DK 089570]
Pancreatic multipotent progenitor cells (MPCs) produce acinar, endocrine and duct cells during organogenesis, but their existence and location in the mature organ remain contentious. We used inducible lineage-tracing from the MPC-instructive gene Ptf1a to define systematically in mice the switch of Ptf1a(+) MPCs to unipotent proacinar competence during the secondary transition, their rapid decline during organogenesis, and absence from the mature organ. Between E11.5 and E15.5, we describe tip epithelium heterogeneity, suggesting that putative Ptf1a(+)Sox9(+)Hnf1 beta(+) MPCs are intermingled with Ptf1a(HI)Sox9(LO) proacinar progenitors. In the adult, pancreatic duct ligation (PDL) caused facultative reactivation of multipotency factors (Sox9 and Hnf1 beta) in Ptf1a(+) acini, which undergo rapid reprogramming to duct cells and longer-term reprogramming to endocrine cells, including insulin(+) beta-cells that are mature by the criteria of producing Pdx1(HI), Nkx6.1(+) and MafA(+). These Ptf1a lineage-derived endocrine/beta-cells are likely formed via Ck19(+)/Hnf1 beta(+)/Sox9(+) ductal and Ngn3(+) endocrine progenitor intermediates. Acinar to endocrine/beta-cell transdifferentiation was enhanced by combining PDL with pharmacological elimination of pre-existing beta-cells. Thus, we show that acinar cells, without exogenously introduced factors, can regain aspects of embryonic multipotentiality under injury, and convert into mature beta-cells.
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