Bone marrow-derived fibroblast precursors mediate ischemic cardiomyopathy in mice

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

Research output: Contribution to journalArticle

258 Scopus citations

Abstract

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 α-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 f ibroblast 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 f ibrosis 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 Fcγ 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.

Original languageEnglish (US)
Pages (from-to)18284-18289
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number48
DOIs
StatePublished - Nov 28 2006
Externally publishedYes

Keywords

  • Fibrosis
  • Heart
  • Monocyte chemoattractant protein 1
  • Monocytes
  • Serum amyloid P

ASJC Scopus subject areas

  • General

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    Haudek, S. B., Xia, Y., Huebener, P., Lee, J. M., Carlson, S., Crawford, J. R., Pilling, D., Gomer, R. H., Trial, J. A., Frangogiannis, N. G., & Entman, M. L. (2006). Bone marrow-derived fibroblast precursors mediate ischemic cardiomyopathy in mice. Proceedings of the National Academy of Sciences of the United States of America, 103(48), 18284-18289. https://doi.org/10.1073/pnas.0608799103