Beta-cell proliferation, but not neogenesis, following 60% partial pancreatectomy is impaired in the absence of FoxM1.

Ackermann Misfeldt A, Costa RH, Gannon M
Diabetes. 2008 57 (11): 3069-77

PMID: 18728229 · PMCID: PMC2570403 · DOI:10.2337/db08-0878

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.

MeSH Terms (12)

Animals Cell Nucleus Size Cell Proliferation Forkhead Box Protein M1 Forkhead Transcription Factors Insulin-Secreting Cells Islets of Langerhans Mice Mice, Inbred C57BL Mice, Inbred Strains Mice, Knockout Pancreatectomy

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