Bone marrow-derived fibroblast precursors mediate ischemic cardiomyopathy in mice. Academic Article uri icon


  • 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.

published proceedings

  • Proc Natl Acad Sci U S A

altmetric score

  • 6

author list (cited authors)

  • Haudek, S. B., Xia, Y., Huebener, P., Lee, J. M., Carlson, S., Crawford, J. R., ... Entman, M. L.

citation count

  • 289

complete list of authors

  • Haudek, Sandra B||Xia, Ying||Huebener, Peter||Lee, John M||Carlson, Signe||Crawford, Jeff R||Pilling, Darrell||Gomer, Richard H||Trial, JoAnn||Frangogiannis, Nikolaos G||Entman, Mark L

publication date

  • November 2006