The development of diabetes in E2f1/E2f2 mutant mice reveals important roles for bone marrow-derived cells in preventing islet cell loss.
Our studies of mice deficient for the E2F1 and E2F2 transcription factors have revealed essential roles for these proteins in the cell cycle control of pancreatic exocrine cells and the regulation of pancreatic beta cell maintenance. Pancreatic exocrine cells in E2f1-/-E2f2 mutant mice become increasingly polyploid with age, coinciding with severe exocrine atrophy. Furthermore, mice deficient for both E2F1 and E2F2 develop nonautoimmune, insulin-dependent diabetes with high penetrance. Surprisingly, transplantation of wild-type bone marrow can prevent or rescue diabetes in E2f1-/-E2f2-/-mice. We hypothesize that exocrine degeneration results in a destructive environment for beta cells, which can be alleviated by restoration of the hematopoietic system that is also defective in E2f1-/-E2f2-/-mice The demonstration that beta cell maintenance under conditions of stress is influenced by bone marrow-derived cells may provide important insight into the design of therapies to boost islet mass and function in diabetic patients.
Li
Feng X
FX
Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA.
Zhu
Jing W
JW
Tessem
Jeffery S
JS
Beilke
Joshua
J
Varella-Garcia
Marileila
M
Jensen
Jan
J
Hogan
Christopher J
CJ
DeGregori
James
J
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001854:Bone Marrow Cells / Q000502:physiology*; D016026:Bone Marrow Transplantation; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D003920:Diabetes Mellitus / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005260:Female; D007328:Insulin / Q000627:therapeutic use; D007515:Islets of Langerhans / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011123:Polyploidy; D012727:Sex Characteristics; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*; D014184:Transplantation, Homologous
D001786:Blood Glucose; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D007328:Insulin; D014157:Transcription Factors