Bone marrow-derived fibroblast precursors mediate ischemic cardiomyopathy in mice

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 ␣-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 Fc␥ 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. fibrosis ͉ heart ͉ monocyte chemoattractant protein 1 ͉ monocytes ͉ serum amyloid P

Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β

“…Fsp1 but not α-smooth muscle actin was found in non-myocyte cells from hypertrophic hearts ( Figure 1C). Activated non-myocyte cells may also be derived from circulating cells (14,(46)(47)(48). Alternatively, the enhanced biomechanical forces resulting from sarcomere protein mutations (7,8) could also provide a local mechanism for activating resident non-myocyte cells.…”

TNF-α–stimulated fibroblasts secrete lumican to promote fibrocyte differentiation

“…Fibrocytes are also found in the scar tissue-like lesions associated with fibrotic diseases such as pulmonary fibrosis, congestive heart failure, cirrhosis of the liver, and nephrogenic systemic fibrosis (3,(7)(8)(9)(10)(11). Fibrocytes express markers of both hematopoietic cells (CD34, CD45, FcγR, LSP-1, MHC class II) and stromal cells (collagens, fibronectin, and matrix metalloproteases) (2,3,(12)(13)(14).…”

Imatinib ameliorates bronchiolitis obliterans via inhibition of fibrocyte migration and differentiation

“…Previous animal studies suggest that differentiation of fibrocytes from circulating monocytes mainly occurs at tissue sites and not in the peripheral blood (17,44,45). A recent study demonstrated that the monocyte-macrophage axis contributed to the development of chronic graft-versus-host disease, including BO (46).…”

“…Fibrocytes represent 0.1-0.5% of the circulating leukocytes that differentiate from monocyte precursors and co-express the leukocyte marker CD45 and mesenchymal markers such as collagen I (15). Fibrocytes act as precursors of fibroblasts that participate in tissue remodeling and also the secretion of inflammatory cytokines, chemokines, and growth factors that contribute to the pathogenesis of fibrotic disorders (16)(17)(18). In lung tissue from BO patients who underwent lung transplantation, increased numbers of fibrocytes are identified in the alveolar parenchyma (19).…”