Hashimoto Naozumi, Jin Hong, Liu Tianju, Chensue Stephen W, Phan Sem H
Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
J Clin Invest. 2004 Jan;113(2):243-52. doi: 10.1172/JCI18847.
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 alpha-smooth muscle actin. Treatment of isolated GFP(+) fibroblasts with TGF-beta 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-1 alpha and secondary lymphoid chemokine, respectively. Thus the collagen-producing lung fibroblasts in pulmonary fibrosis can also be derived from BM progenitor cells.
肺纤维化中，成纤维细胞的起源一般认为是肺内源性的，但它们的肺外起源，尤其是源自骨髓（BM）祖细胞的可能性尚未被排除。为了直接检验这种可能性，将从表达增强型绿色荧光蛋白（GFP）的转基因小鼠中分离得到的骨髓持久移植到成年小鼠体内。通过气管内注射博来霉素（BLM）在这些嵌合小鼠中诱导肺纤维化，导致大量GFP（+）细胞出现在活跃的纤维化病灶中，而在对照肺中只能鉴定出少数GFP（+）细胞。对肺细胞进行流式细胞术分析证实，嵌合小鼠中BLM诱导GFP（+）细胞增加，并显示同时表达I型胶原的GFP（+）细胞显著增加。从嵌合小鼠中分离出的GFP（+）肺成纤维细胞表达胶原和端粒酶逆转录酶，但不表达α-平滑肌肌动蛋白。用转化生长因子-β（TGF-β）处理分离出的GFP（+）成纤维细胞未能诱导其向肌成纤维细胞分化。培养的肺成纤维细胞表达趋化因子受体CXCR4和CCR7，并分别对其同源配体基质细胞衍生因子-1α和二级淋巴趋化因子产生趋化反应。因此，肺纤维化中产生胶原的肺成纤维细胞也可源自BM祖细胞。
