Masataka Sata1, Yasunobu Hirata, Ryozo Nagai. 1. Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033.
Abstract
BACKGROUND: Despite recent advances in immunosuppressive therapy, accelerated coronary atherosclerosis remains a major problem in the long-term survival of cardiac transplant recipients. However, the pathogenesis of the transplant-associated atherosclerosis remains largely unknown. METHODS AND RESULTS: The origin of the neointimal cells was investigated by heterotopic heart transplantation between the wild-type mouse and the ROSA26 mouse that expresses LacZ ubiquitously (LacZ-mouse). Coronary arteries of the cardiac allograft developed neointimal hyperplasia consisting of alpha-smooth muscle actin-positive cells. When a heart from a wild-type mouse was transplanted into a LacZ-mouse, most of the neointimal cells expressed LacZ whereas the medial cells were negative. In contrast, when a heart from a LacZ-mouse was transplanted into a wild-type mouse, most of the neointimal cells were negative for LacZ whereas the medial cells expressed LacZ. In situ hybridization of the allografts from female to male mice revealed that most of the neointimal cells corresponded to cells from the recipients. CONCLUSIONS: Blood cells include progenitors of smooth muscle cells, which attach to the graft endothelia, differentiate into smooth muscle cells and proliferate, thus contributing to neointima formation. Our findings suggest a new therapeutic strategy that involves targeting of homing, differentiation and proliferation of putative smooth muscle progenitor cells to prevent proliferative vascular diseases.
BACKGROUND: Despite recent advances in immunosuppressive therapy, accelerated coronary atherosclerosis remains a major problem in the long-term survival of cardiac transplant recipients. However, the pathogenesis of the transplant-associated atherosclerosis remains largely unknown. METHODS AND RESULTS: The origin of the neointimal cells was investigated by heterotopic heart transplantation between the wild-type mouse and the ROSA26mouse that expresses LacZ ubiquitously (LacZ-mouse). Coronary arteries of the cardiac allograft developed neointimal hyperplasia consisting of alpha-smooth muscle actin-positive cells. When a heart from a wild-type mouse was transplanted into a LacZ-mouse, most of the neointimal cells expressed LacZ whereas the medial cells were negative. In contrast, when a heart from a LacZ-mouse was transplanted into a wild-type mouse, most of the neointimal cells were negative for LacZ whereas the medial cells expressed LacZ. In situ hybridization of the allografts from female to male mice revealed that most of the neointimal cells corresponded to cells from the recipients. CONCLUSIONS: Blood cells include progenitors of smooth muscle cells, which attach to the graft endothelia, differentiate into smooth muscle cells and proliferate, thus contributing to neointima formation. Our findings suggest a new therapeutic strategy that involves targeting of homing, differentiation and proliferation of putative smooth muscle progenitor cells to prevent proliferative vascular diseases.