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 5

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Characterization of cultured lung fibroblasts. Lung fibroblasts isolated...
Characterization of cultured lung fibroblasts. Lung fibroblasts isolated from BLM-treated GFP BM chimera mice were analyzed by fluorescence microscopy (a–f). The cells showed typical fibroblast morphology, many being stellate or spindle-shaped (a). An average 80% of these cells expressed GFP (green fluorescence in a, at ×100; inset at ×400). Cells were stained with both anti-GFP (green) and anti–Col I (red) antibodies in b–d. The same microscopic field was photographed with the green (b) or red (c) filter only, or both simultaneously (d). Colocalization of both GFP and Col I expression resulted in a yellow color in d. Inset in d shows the cells stained with anti-GFP antibody (green) and isotype-matched control IgG for Col I (red). Cells were also stained with both anti-GFP (green) and anti–α-SMA (red) antibodies (e). Colocalization of GFP and α-SMA should appear yellow, but the two α-SMA+ cells in this field did not appear to express GFP (e). Finally, cells were also stained with anti-GFP (green) and anti-TERT (red) antibodies. Colocalization of GFP and TERT appeared yellow, and most of the cells in this field expressed both TERT and GFP (f). Magnification was ×200 for b–f. A representative example of at least three independent experiments is shown.