Fc receptor engagement mediates differentiation of cardiac fibroblast precursor cells

Sandra B. Haudek, Jo Ann Trial, Ying Xia, Damon Gupta, Darrell Pilling, Mark L. Entman

Research output: Contribution to journalArticlepeer-review

86 Scopus citations

Abstract

We previously described a critical role for a fibroblast precursor population in the development of a murine fibrotic cardiomyopathy model (I/RC). These precursors arose from circulating bone marrow-derived cells of monocytic origin. Administration of serum amyloid P (SAP) prevented the presence of this cell population in the heart and the cardiomyopathy. Because SAP binds to Fc receptors (FcRs) expressed on monocytes, we investigated the involvement of FcR signaling. We chose mice lacking the FcRγ chain protein (FcRγ-/-), a common membrane-signaling component of activating FcRs. Like wild-type mice, FcRγ-/- mice developed fibrosis and cardiac dysfunction when subjected to I/RC. However, unlike wild-type mice, SAP in FcRγ-/- mice failed to inhibit the development of fibrosis and cardiac dysfunction and did not diminish the numbers of α-smooth muscle actin+ and CD34+, CD45+ fibroblasts that were typical for I/RC. To further examine the role of SAP in monocyte-to-fibroblast transition, we performed in vitro assays in which human peripheral blood mononuclear cells (PBMCs) migrated through human umbilical vein endothelial cells (HUVECs). We found that MCP-1-dependent transendothelial migration of monocytes markedly accelerated their differentiation into fibroblasts. This monocyte differentiation to fibroblasts was eliminated when SAP was added to the PBMC suspension before endothelial transmigration. Adding SAP to cells after successful migration did not inhibit fibroblast maturation. These data indicate that SAP inhibits the differentiation of a blood-borne, myeloid cell population into fibroblasts by signaling through activating FcRs before transendothelial migration has occurred. We suggest that FcR activation of circulating precursor cells may represent a new treatment target for adverse remodeling and cardiac fibrosis.

Original languageEnglish (US)
Pages (from-to)10179-10184
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number29
DOIs
StatePublished - Jul 22 2008

Keywords

  • Endothelial transmigration
  • Fibrosis
  • Heart
  • Monocytes
  • Serum amyloid P

ASJC Scopus subject areas

  • General

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