Role of Stem Cell Factor and Bone Marrow-Derived Fibroblasts in Airway Remodeling

Abstract

Recent evidence suggests that bone marrow-derived fibroblasts are involved in airway remodeling in asthma, but the role and mechanism of recruitment of these fibroblasts remains unclear. Stem cell factor (SCF), a key factor in the propagation of hematopoietic stem cells, is important in the process of airway remodeling as well. To test the hypothesis that SCF is involved in the recruitment and differentiation of bone marrow-derived progenitor cells, GFP-bone marrow chimeric mice were created. These mice were then sensitized and chronically challenged with cockroach antigen to induce chronic airway disease. Fluorescence microscopy revealed an influx of significant numbers of GFP-expressing fibroblasts in the airways of these mice, which was confirmed by flow cytometric analysis of cells co-expressing both GFP and collagen I. These cells preferentially expressed c-kit, interleukin-31 receptor, and telomerase reverse transcriptase when compared with control lung-derived fibroblasts. Interestingly, SCF stimulated interleukin-31 receptor expression in bone marrow cells, whereas interleukin-31 strongly induced telomerase reverse transcriptase expression in fibroblasts. Treatment with neutralizing antibodies to SCF significantly reduced airway remodeling and suppressed the recruitment of these bone marrow-derived cells to the lung. Thus SCF in conjunction with interleukin-31 may play a significant role in airway remodeling by promoting the recruitment of bone marrow-derived fibroblast precursors into the lung with the capacity to promote lung myofibroblast differentiation. (Am J

Resident Tissue-Specific Mesenchymal Progenitor Cells Contribute to Fibrogenesis in Human Lung Allografts

“…Thus, these data demonstrating a lung, rather than a BM, origin of myofibroblasts support the studies of BM chimeric animals, in which, despite evidence of recruitment of BM-derived fibroblasts to remodeling lung, myofibroblasts present in the fibrotic lesions were not derived from BM progenitors. 41,42 Our human studies also complement the recent elegant animal studies 43 of gene-labeled mice demonstrating local tissue resident mesenchymal, rather than epithelial, cells as precursors of collagen-secreting myofibroblasts in the kidney. Interestingly, the fibrotic cells in these kidney injury models arose from resident cells expressing FoxD1, the forkhead transcription factor seen in embryonic mesenchyme fated to become stromal cells of the kidney.…”

Mesenchymal Stem Cells Require MARCKS Protein for Directed Chemotaxis In Vitro

“…Accordingly, our results show that the chemotactic agents C5a and SDF-1a induce a rapid MARCKS phosphorylation by 30 seconds after exposure (Figure 3). Interestingly, SCF, which has been speculated to act as a chemoattractant for mesenchymal cells in vivo (22), did not induce chemotaxis by BM-MSCs. Inasmuch as SCF is a potent factor in inflammatory cell attraction and maintenance of lung airway inflammation (22,35), these findings were surprising.…”

“…Interestingly, SCF, which has been speculated to act as a chemoattractant for mesenchymal cells in vivo (22), did not induce chemotaxis by BM-MSCs. Inasmuch as SCF is a potent factor in inflammatory cell attraction and maintenance of lung airway inflammation (22,35), these findings were surprising. SCF also did not affect MARCKS phosphorylation, providing additional evidence that phosphorylation of MARCKS is an important component of stem cell migration.…”

Effect of Imatinib on Airway Smooth Muscle Thickening in a Murine Model of Chronic Asthma

“…[39]. In murine asthma models, in vivo neutralization of SCF attenuates airway remodeling [21,40]; however, few data are available about the effect of imatinib on SCF levels.…”