Fusion of proinsulin-producing bone marrow-derived cells with hepatocytes in diabetes.
We previously reported that diabetes in mice is associated with the appearance of proinsulin-producing (Proins-P) cells in the liver. It was unclear, however, whether these Proins-P bone marrow-derived cells (BMDC) merely transit through the liver or undergo fusion with hepatocytes, normally an extremely rare event. In this study, we found that, in diabetes, BMDC in the liver produce not only Proins but also TNF-alpha, suggesting that diabetes reprograms gene expression in BMDC, turning on "inappropriate" genes. Bone marrow transplantation using genetically marked donor and recipient mice showed that fusion occurs between Proins-P BMDC and hepatocytes. Cell fusion is further supported by the presence of the Y chromosome in Proins-P cells in female mice that received male bone marrow transplantation cells. Morphologically, Proins-P fusion cells are albumin-producing hepatocytes that constitute approximately 2.5% of the liver section area 5 months after diabetes induction. An extensive search failed to reveal any fusion cells in nondiabetic mice. Thus, diabetes causes fusion between Proins-P BMDC and hepatocytes in vivo, an observation that has implications for the pathophysiology of diabetes as well as the fundamental biology of heterotypic cell fusion.
Fujimiya
Mineko
M
Department of Anatomy, Section of Endocrinology and Metabolism, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
Kojima
Hideto
H
Ichinose
Masumi
M
Arai
Ryohachi
R
Kimura
Hiroshi
H
Kashiwagi
Atsunori
A
Chan
Lawrence
L
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000378:metabolism; D005260:Female; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D017404:In Situ Hybridization, Fluorescence; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D011384:Proinsulin / Q000096:biosynthesis*; D012737:Sex Factors
D011384:Proinsulin