Bone marrow–derived progenitor cells in pulmonary fibrosis
Naozumi Hashimoto, … , Stephen W. Chensue, Sem H. Phan
Naozumi Hashimoto, … , Stephen W. Chensue, Sem H. Phan
Published January 15, 2004
Citation Information: J Clin Invest. 2004;113(2):243-252. https://doi.org/10.1172/JCI18847.
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Article Cell biology

Bone marrow–derived progenitor cells in pulmonary fibrosis

Abstract

The origin of fibroblasts in pulmonary fibrosis is assumed to be intrapulmonary, but their extrapulmonary origin and especially derivation from bone marrow (BM) progenitor cells has not been ruled out. To examine this possibility directly, adult mice were durably engrafted with BM isolated from transgenic mice expressing enhanced GFP. Induction of pulmonary fibrosis in such chimera mice by endotracheal bleomycin (BLM) injection caused large numbers of GFP+ cells to appear in active fibrotic lesions, while only a few GFP+ cells could be identified in control lungs. Flow-cytometric analysis of lung cells confirmed the BLM-induced increase in GFP+ cells in chimera mice and revealed a significant increase in GFP+ cells that also express type I collagen. GFP+ lung fibroblasts isolated from chimera mice expressed collagen and telomerase reverse transcriptase but not α-smooth muscle actin. Treatment of isolated GFP+ fibroblasts with TGF-β failed to induce myofibroblast differentiation. Cultured lung fibroblasts expressed the chemokine receptors CXCR4 and CCR7 and responded chemotactically to their cognate ligands, stromal cell–derived factor-1α and secondary lymphoid chemokine, respectively. Thus the collagen-producing lung fibroblasts in pulmonary fibrosis can also be derived from BM progenitor cells.

Authors

Naozumi Hashimoto, Hong Jin, Tianju Liu, Stephen W. Chensue, Sem H. Phan

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Figure 4

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Flow-cytometric analysis of whole-lung cells from GFP BM chimera mice. W...
Flow-cytometric analysis of whole-lung cells from GFP BM chimera mice. Whole-lung cells were isolated from BLM-treated (a and c) or saline-treated (b and d) GFP BM chimera mice at day 21 after BLM or saline treatment. Following the appropriate immunostaining, the cells were analyzed by flow cytometry for GFP and Col I expression (c and d) after gating on intact live cells (region indicated by R1) according to side scatter (shown in logarithmic scale, ssLOG) and forward scatter (FS) (a and b). Results of analysis of cells treated with isotype-matched control IgG for the anti–Col I antibody are shown in the insets in c and d. Furthermore, the GFP+ cells from these BLM-treated mice were analyzed for Col I and F4/80 or Mac-3 expression after gating on GFP+ cells in the R1 region (region indicated by R2 in the inset in e) (e and f). The Col I+ and F4/80+ cells represented 2.7% ± 0.76% of GFP+ cells (e). The Col I+ and Mac-3+ cells represented 5.5% ± 0.4% of GFP+ cells (f). Inset in f shows the cells stained with isotype-matched control IgG. Representative runs are shown for each group from a total of eight BLM-treated or saline-treated GFP BM chimera mice, respectively. The quantitative results are summarized in Table 1.