Bone marrow–derived progenitor cells in pulmonary fibrosis

TLDR

Pulmonary fibrosis fibroblasts are presumed intrapulmonary, yet bone marrow progenitor contribution has not been excluded. The study aimed to test whether bone marrow progenitor cells can become pulmonary fibrosis fibroblasts. Adult mice were engrafted with GFP‑labeled bone marrow, fibrosis induced by bleomycin, and GFP+ lung fibroblasts were analyzed for chemokine receptor expression and chemotactic response. Bleomycin caused a large increase of GFP+ collagen‑producing fibroblasts that expressed CXCR4/CCR7 but not α‑SMA, did not respond to TGF‑β with myofibroblast differentiation, demonstrating that bone marrow progenitors contribute to collagen‑producing fibroblasts 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.