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 (Foxm1^flox/flox;Pdx1-Cre [FoxM1^Δpanc]) 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, β-cell mass, proliferation, β-cell size, islet size, islet density, and Neurogenin3 expression were analyzed.

Results: In Control mice, PPx stimulated β-cell proliferation and neogenesis and up-regulated Foxm1 and several of its known targets (Plk1, Cenp-a, Birc5/Survivin, 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, FoxM1^Δpanc 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 pre-existing β-cells.