β-Cell Proliferation, but Not Neogenesis, Following 60% Partial Pancreatectomy Is Impaired in the Absence of FoxM1

Abstract

OBJECTIVE: This study was designed to determine whether the transcription factor FoxM1 was required for regeneration of beta-cell mass via proliferation and/or neogenesis in the adult after 60% partial pancreatectomy (PPx). RESEARCH DESIGN AND METHODS: Adult mice with a pancreas-wide deletion of Foxm1 (Foxm1(flox/flox);Pdx1-Cre [FoxM1(Deltapanc)]) and their control littermates (Foxm1(flox/flox)) were subjected to PPx or a sham operation, after which islet expression of Foxm1 and several target genes, beta-cell mass, proliferation, beta-cell size, islet size, islet density, and neurogenin-3 expression were analyzed. RESULTS: In control mice, PPx stimulated beta-cell proliferation and neogenesis and upregulated Foxm1 and several of its known targets (Plk1, Cenp-a, Birc5/Survivin, and Ccnb1) in islets. Within 1 week post-PPx, control mice underwent significant regeneration of beta-cell mass, and average islet size within the regenerating lobe was similar to that after a sham operation. However, FoxM1(Deltapanc) mice exhibited specific impairments in beta-cell mass regeneration and islet growth after PPx, with reduced proliferation of alpha- and beta-cells but no impairments in acinar or ductal cell proliferation. Interestingly, FoxM1 was not required for proliferation of beta-cells within small endocrine cell clusters located in the regenerating portion of the pancreas but was specifically required for proliferation of beta-cells within larger islets. Additionally, FoxM1 was not required for beta-cell neogenesis following PPx. CONCLUSIONS: Our results indicate that FoxM1 is partially required for increased beta-cell proliferation, but not beta-cell neogenesis, stimulated by PPx. Furthermore, FoxM1 seems to be dispensable for proliferation of beta-cells following neogenesis but is required for proliferation of preexisting beta-cells.