title: Bmi1 is required for regeneration of the exocrine pancreas in mice.
abstract: OBJECTIVE
  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.
authors.affiliation: Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, California.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Fukuda
authors.affiliation: Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, California.
authors.forename: John P
authors.initials: JP
authors.lastname: Morris
authors.affiliation: Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, California. Electronic address: mhebrok@diabetes.ucsf.edu.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hebrok
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D049109:Cell Proliferation; D002108:Ceruletide; D002796:Choline Deficiency / Q000150:complications; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005001:Ethionine; D005260:Female; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D046790:Pancreas, Exocrine / Q000378:metabolism* / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D046509:Tissue Culture Techniques; D018183:Transplantation Chimera; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C489421:Bmi1 protein, mouse; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D049452:Green Fluorescent Proteins; D002108:Ceruletide; D063150:Polycomb Repressive Complex 1; D005001:Ethionine