Bone marrow-derived fibroblast precursors mediate ischemic cardiomyopathy in mice.
We previously described a mouse model of fibrotic ischemia/reperfusion cardiomyopathy (I/RC) arising from daily, brief coronary occlusion. One characteristic of I/RC was the prolonged elevation of monocyte chemoattractant protein 1 (MCP-1), which was obligate to its phenotype and may contribute to the uptake of bloodborne cells. Here we describe in I/RC hearts a population of small spindle-shaped fibroblasts that were highly proliferative and expressed collagen I and alpha-smooth muscle actin (myofibroblast markers), CD34 (a precursor marker), and CD45 (a hematopoietic marker). These cells represented 3% of all nonmyocyte live cells. To confirm the cells' bone marrow origin, chimeric mice were created by the rescue of irradiated C57BL/6 mice with marrow from ROSA26, a congenic line expressing lacZ. I/RC resulted in a large population of spindle-shaped fibroblasts containing lacZ. We postulated that the fibroblast precursors represented a developmental path for a subset of monocytes, whose phenotype we have shown to be influenced by serum amyloid P (SAP). Thus, we administered SAP in vivo, which markedly reduced the number of proliferative spindle-shaped fibroblasts and completely prevented I/RC-induced fibrosis and global ventricular dysfunction. By contrast, SAP did not suppress the inflammation or chemokine expression seen in I/RC. SAP, a member of the pentraxin family, binds to Fcgamma receptors and modifies the pathophysiological function of monocytes. Our data suggest that SAP interferes with assumption of a fibroblast phenotype in a subset of monocytes and that SAP may be an important regulator in the linkage between inflammation and nonadaptive fibrosis in the heart.
Haudek
Sandra B
SB
DeBakey Heart Center, Baylor College of Medicine, Methodist Hospital, Houston, TX 77030, USA.
Xia
Ying
Y
Huebener
Peter
P
Lee
John M
JM
Carlson
Signe
S
Crawford
Jeff R
JR
Pilling
Darrell
D
Gomer
Richard H
RH
Trial
JoAnn
J
Frangogiannis
Nikolaos G
NG
Entman
Mark L
ML
D000682:Amyloid / Q000378:metabolism; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology*; D009202:Cardiomyopathies / Q000473:pathology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D002678:Chimera; D004195:Disease Models, Animal; D005347:Fibroblasts; D005355:Fibrosis / Q000473:pathology*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D017202:Myocardial Ischemia / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics
D000682:Amyloid; D018952:Antigens, CD34; D012333:RNA, Messenger; D017493:Leukocyte Common Antigens