Whence Cometh Neointimal Myofibroblasts?

Whence Cometh Neointimal Myofibroblasts? To the Editor: We greatly enjoyed the elegant and informative study recently published by Shi and colleagues. Using bromodeoxyuridine (BrdU) labeling after severe endoluminal coronary artery injury, the authors demonstrated activation and proliferation of porcine adventitial fibroblasts that initially lacked actin expression. Subsequently, the adventitial fibroblasts acquired actin expression indicative of myofibroblastic differentiation, and these proliferating adventitia-derived myofibroblasts were then shown to translocate the gap between dissected media to contribute to neointima formation. Smaller numbers of similar BrdU-positive nonmuscle cells were demonstrated in the media as well. In their discussion, the authors note that the precise mechanisms regulating fibroblast migration to neointima are unknown. It has been our experience and that of others in human material that endothelium and perivascular adventitial and interstitial stromal dendritic fibroblast-like cells express CD34, a transmembrane glycoprotein known as the hematopoietic progenitor cell antigen. It is increasingly thought that these cells are uncommitted stromal reserve cells that, we feel, constitute the raw material of the microvascular unit for use in repair, stromal remodeling, and homeostasis. CD34 has a glycocalyceal mucin domain that is a ligand for integrins, and thus CD34 may be involved in regulating proadhesive and antiadhesive cellular behavior. The intracytoplasmic domain of the molecule is probably involved in signal transduction and cellular differentiation and therefore might be involved in regulation of phenotypic plasticity of CD34-positive adventitial fibroblasts engaged in myofibroblastic differentiation. We have also shown CD31 positive endothelial differentiation of CD34-positive dendritic cells in cardiac myxomas. In addition to being concentrated in the adventitia, CD34-positive fibroblasts are also interspersed among the medial smooth muscle cells in some vessels (personal observations). Thus, the distribution of CD34-positive fibroblasts in human vessels is similar to the distribution of BrdU-labeled adventitial and scattered medial cells in the porcine material of Shi et al. In studies of myofibroblastic differentiation of CD34-positive stromal cells in mammary stromal tumors and in fibroma of tendon sheath, we noted that increasing actin expression in the tumor cells often correlated with CD34 downregulation. We wonder whether studying CD34 expression in the porcine material of Shi et al might further elucidate the molecular basis of adventitial myofibroblast differentiation and migration in medial injury repair and neointima formation. We are also interested in the role of dendritic stromal histiocytes that express coagulation FXIIIa, the so-called collagen-associated dendrophages of Nickoloff, in matrix remodeling and stromal repair as well as in morphogenesis and tumors. Transglutaminase FXIIIa is a potent and pleiotropic fibroblast growth factor that regulates both fibroblast proliferation and matrix protein synthesis and catalyzes polymerization of matrix proteins including fibrin, fibronectin, and collagens. FXIIIa coated on plastic causes formation of actin-positive stress fibers in fibroblasts, modulates novel cell spreading and adhesive behavior in fibroblasts and other similarly grown normal and neoplastic cells, and induces phosphorylation of tyrosine residues in 120and 70-kD proteins in these fibroblasts. Most normal connective tissue contains scattered microvascular adventitial FXIIIa-positive dendrophages, and these cells are often markedly increased in inflammatory and reparative processes. FXIIIa-positive dendrophages combine with CD34-positive dendritic cells in a variety of mesenchymal tumors, including the quasithrombotic neoplasm cardiac myxoma. Thus, we suggest that examination of the material of Shi et al from the standpoint of FXIIIa reactivity to detect these important mitogenic microvascular cells might also be informative with regard to the mechanisms of myofibroblast differentiation and matrix remodeling in neointima formation. In conclusion, we applaud the excellent study of Shi and colleagues and look forward to further molecular investigations into the processes of microvascular myofibroblast differentiation and migration implicit in their results.