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 6

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Chemokine and chemokine receptor expression, and fibroblast migration. L...
Chemokine and chemokine receptor expression, and fibroblast migration. Lung RNA from saline-treated or BLM-treated mice were obtained at the indicated time points (days after saline or BLM treatment, with day 0 indicating pretreatment values) and analyzed for SDF-1α (a) and SLC (b) mRNA using real-time PCR. Data shown at each time point represent the means ± SD from six BLM-treated or saline-treated mice, respectively, and are representative of two independent experiments. (c) Results of RT-PCR analysis for CXCR4 and CCR7 mRNA in cultured BLF or SLF. The left panel in c shows a representative electropherogram of the indicated products using RNA samples from: spleen (lane 1), BLF (lanes 2–4), and SLF (lanes 5–7). The right panel in c summarizes the quantitative results after normalization to the GAPDH signal. Data shown represent the means ± SD (n = 3), and are representative of three independent experiments. BLF were analyzed for migratory activity toward the indicated chemokine (d). Additions to the upper (where cells were loaded) or lower chamber were as indicated. Both SLC and SDF-1α were chemotactic for lung fibroblasts, and SDF-1α was also weakly chemokinetic. Data shown represent means ± SD. The experiment was repeated once with similar results. Asterisks signify statistically significant difference (P < 0.05) between the two groups indicated by connecting lines above the respective bars.