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 β-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 (Foxm1flox/flox;Pdx1-Cre [FoxM1Δpanc]) and their control littermates (Foxm1flox/flox) were subjected to PPx or a sham operation, after which islet expression of Foxm1 and several target genes, β-cell mass, proliferation, β-cell size, islet size, islet density, and neurogenin-3 expression were analyzed. RESULTS—In control mice, PPx stimulated β-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 β-cell mass, and average islet size within the regenerating lobe was similar to that after a sham operation. However, FoxM1Δpanc mice exhibited specific impairments in β-cell mass regeneration and islet growth after PPx, with reduced proliferation of α- and β-cells but no impairments in acinar or ductal cell proliferation. Interestingly, FoxM1 was not required for proliferation of β-cells within small endocrine cell clusters located in the regenerating portion of the pancreas but was specifically required for proliferation of β-cells within larger islets. Additionally, FoxM1 was not required for β-cell neogenesis following PPx. CONCLUSIONS—Our results indicate that FoxM1 is partially required for increased β-cell proliferation, but not β-cell neogenesis, stimulated by PPx. Furthermore, FoxM1 seems to be dispensable for proliferation of β-cells following neogenesis but is required for proliferation of preexisting β-cells.