Bmi1 is required for regeneration of the exocrine pancreas in mice

Gastroenterology. 2012 Sep;143(3):821-831.e2. doi: 10.1053/j.gastro.2012.05.009. Epub 2012 May 17.

Abstract

Background & aims: Bmi1 is a member of the Polycomb protein family and represses transcription by modifying chromatin organization at specific promoters. Bmi1 is implicated in the control of stem cell self-renewal and has been shown to regulate cell proliferation, tissue homeostasis, and differentiation. Bmi1 is present in a subpopulation of self-renewing pancreatic acinar cells and is expressed in response to pancreatic damage. We investigated the role of Bmi1 in regeneration of exocrine pancreas.

Methods: Acute pancreatitis was induced in Bmi1(-/-) mice with cerulein; pancreatic cell regeneration, differentiation, and apoptosis were assessed. Cultured Bmi1(-/-) and wild-type primary acini were analyzed in vitro to determine acinar-specific consequences of Bmi1 deletion. To investigate cell autonomous versus non-cell autonomous roles for Bmi1 in vivo, pancreatitis was induced in Bmi1(-/-) mice reconstituted with a wild-type hematopoietic system.

Results: Bmi1 expression was up-regulated in the exocrine pancreas during regeneration after cerulein-induced pancreatitis. Exocrine regeneration was impaired following administration of cerulein to Bmi1(-/-) mice. Pancreata of Bmi1(-/-) mice were hypoplastic, and the exocrine pancreas was replaced with ductal metaplasia that had increased apoptosis and decreased cell proliferation compared with that of wild-type mice. Expression of Cdkn2a and p53-dependent apoptotic genes was markedly up-regulated in Bmi1(-/-) pancreas compared with wild-type mice after injury. Furthermore, after transplantation of bone marrow from wild-type to Bmi1(-/-) mice, the chimeric mice had intermediate levels of pancreatic hypoplasia and significant but incomplete rescue of impaired exocrine regeneration after cerulein injury.

Conclusions: Bmi1 contributes to regeneration of the exocrine pancreas after cerulein-induced injury through cell autonomous mechanisms, in part by regulating Cdkn2a expression, and non-cell autonomous mechanisms.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Apoptosis
  • Bone Marrow Transplantation
  • Cell Differentiation
  • Cell Proliferation*
  • Ceruletide
  • Choline Deficiency / complications
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Disease Models, Animal
  • Ethionine
  • Female
  • Gene Expression Regulation
  • Green Fluorescent Proteins / biosynthesis
  • Green Fluorescent Proteins / genetics
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Pancreas, Exocrine / metabolism*
  • Pancreas, Exocrine / pathology
  • Pancreatitis / chemically induced
  • Pancreatitis / genetics
  • Pancreatitis / metabolism*
  • Pancreatitis / pathology
  • Polycomb Repressive Complex 1
  • Proto-Oncogene Proteins / deficiency
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Regeneration*
  • Repressor Proteins / deficiency
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Time Factors
  • Tissue Culture Techniques
  • Transplantation Chimera
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Bmi1 protein, mouse
  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • Tumor Suppressor Protein p53
  • Green Fluorescent Proteins
  • Ceruletide
  • Polycomb Repressive Complex 1
  • Ethionine