Response to Letter Regarding Article, “CC Chemokine Receptor-1 Activates Intimal Smooth Muscle–Like Cells in Graft Arterial Disease”
To the Editor:
The comments by Lee are well taken. Our study on graft arterial disease has primarily emphasized that the intimal smooth muscle cells (SMLCs) are distinct from medial smooth muscle cells.1 Indeed, we believe that SMLCs likely consist of multiple lineages instead of a single cell source. As we showed previously, candidate precursor cells of the intimal SMLCs include medial smooth muscle cells, bone marrow–derived cells, endothelial cell transdifferentiation, fibroblasts, tissue-derived stem cells, or hematopoietic inflammatory cells.2 We also agree that fibrocytes may contribute to the SMLC population. We have not formally explored whether fibrocytes can differentiate into intimal SMLCs, but this possibility merits consideration. Regardless, SMLC precursors of bone marrow origin (eg, fibrocytes) constitute <20% of the total intimal SMLC population in the graft arterial disease lesion of murine aortic transplantation without immunosuppression.3
Fibroblasts are spindle-shaped cells expressing vimentin in the absence of desmin and smooth muscle α-actin. Fibroblasts exist as several morphological phenotypes ranging from the “noncontractile” fibroblast to the “contractile” myofibroblast, with intermediate phenotypes such as the protomyofibroblast. Myofibroblasts expressing smooth muscle α-actin and stress fibers are further distinguished from smooth muscle cells by their lack of desmin and smooth muscle myosin. Fibroblasts/myofibroblasts may originate from a variety of sources, including modulation of epithelial cells (epithelial-mesenchymal transition), bone marrow–derived fibrocytes, or tissue-derived mesenchymal stem cells. Murine bone marrow–derived lung fibroblasts express CXC motif-chemokine receptor 4 (CXCR4) and CC motif-chemokine receptor 7 (CCR7) and respond chemotactically to their cognate ligands.4
Fibrocytes are spindle-shaped cells uniquely expressing smooth muscle α-actin, vimentin, collagen I and III, fibronectin, CD11b, CD13, CD18, CD34, and CD45. Transforming growth factor-β with endothelin-1 can differentiate CD14+ mononuclear cell–derived fibrocytes into myofibroblast-like cells. Human peripheral fibrocytes express CCR5, CCR7, and CXCR4; murine peripheral fibrocytes express CCR7 and CXCR4; and murine lung fibrocytes express modest levels of CCR1 and CXCR4 and high levels of CCR2, CCR5, and CCR7.5 CC motif-chemokine ligand 2, monocyte chemotactic protein-1, and transforming growth factor-β1 increase collagen I production in lung fibrocytes. These findings indicate that fibroblasts/myofibroblasts and fibrocytes express unique functional chemokine receptors, suggesting that their cognate ligands likely contribute to migration and/or proliferation in an inflammatory environment. It remains uncertain whether fibroblasts/myofibroblasts can differentiate into smooth muscle cells and/or intimal SMLCs. Bone marrow is not the dominant site of origin for SMLCs. Thus, if fibrocytes serve as significant contributors, they may derive from places other than bone marrow. We agree fully that future research should evaluate carefully the various cell lineages of intimal SMLCs in graft arterial disease and atherosclerotic lesions, including origin from fibrocytes.
We thank D. Cameron, S. Jang, and E. Simon-Morrissey for their technical expertise and S. Karwacki for editorial assistance.
Sources of Funding
This work was supported by an American Society of Transplantation Faculty Development Grant (Dr Shimizu), American Heart Association Scientist Development Grant (Dr Shimizu), a Brigham and Women’s Hospital Biomedical Institute Funds to Research Excellence grant (Dr Mitchell), and grants from the Donald W. Reynolds Foundation (Dr Libby) and the National Institutes of Health (HL-34636 to Drs Libby and Minami and HL-083154 to Dr Lopez-Ilasaca).