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The bone marrow leaves its scar: new concepts in pulmonary fibrosis
Sarah E. Dunsmore and Steven D. Shapiro
Respiratory and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
Address correspondence to: Steven D. Shapiro, Respiratory and Clinical Care Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA. Phone: (617) 732-7599; Fax: (617) 232-4623; E-mail: sshapiro@rics.bwh.harvard.edu.
Find articles by Dunsmore, S. in: JCI | PubMed | Google Scholar
Respiratory and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
Address correspondence to: Steven D. Shapiro, Respiratory and Clinical Care Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA. Phone: (617) 732-7599; Fax: (617) 232-4623; E-mail: sshapiro@rics.bwh.harvard.edu.
Find articles by Shapiro, S. in: JCI | PubMed | Google Scholar
Published January 15, 2004 - More info
J Clin Invest. 2004;113(2):180–182. https://doi.org/10.1172/JCI20782.
© 2004 The American Society for Clinical Investigation
Idiopathic pulmonary fibrosis (IPF) is a devastating disorder with no effective treatment, which insidiously advances to airspace obliteration and death. The mean survival time following diagnosis is less than 5 years. Pathologically, the disease is characterized by chronic inflammation and exuberant collagen production within the lung (1). Survival can be predicted by the extent of fibroblastic foci (Figure 1) present at the time of lung biopsy (2). While the role of inflammation in IPF is less clear, inflammatory mediators, particularly TGF-β, are presumed to drive the fibrotic process. Myofibroblasts, a distinguishing feature of fibroblastic foci (3), are thought to arise from local activation of parenchymal fibroblasts by TGF-β and are historically considered to be the primary collagen-producing cell in fibrotic lesions (3, 4).
Figure 1Origin of fibroblastic foci. Fibroblastic foci, sites of active collagen synthesis, are the pathologic hallmark of pulmonary fibrosis. The traditional view is that cytokine secretion by epithelial and inflammatory cells induces parenchymal lung fibroblasts to overproduce collagen and to differentiate into myofibroblasts. Several recent studies indicate that bone marrow–derived cells can engraft into lung tissue and produce collagen. Bone marrow–derived cells may be recruited to the lung by chemokines generated by macrophages.
In this issue of the JCI, Hashimoto and colleagues (5) strongly force us to reconsider these fundamental concepts regarding the origin and phenotype of pathologic fibroblasts. In this study, the authors experimentally induced pulmonary fibrosis via bleomycin administration to mice that had been reconstituted with bone marrow derived from GFP transgenic mice. Thus, in the reconstituted mice, cells derived from bone marrow precursors will express GFP, and resident cells will not. Most of the collagen-producing fibroblasts observed in the lungs of these mice were of bone marrow rather than of local origin. Interestingly, GFP-positive fibroblasts could not be induced by TGF-β to express α-smooth muscle actin. Therefore, the pathologic collagen-producing fibroblasts not only were bone marrow–derived but were incapable of transforming into myofibroblasts.
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Bone marrow–derived stem cells
Recent literature indicates that the pluripotency of bone marrow–derived cells extends further than classic hematopoietic differentiation (Figure 2). Studies have shown that bone marrow–derived stromal cells (7) and hematopoietic precursors (8) engraft and become structural cells, including fibroblasts, particularly following tissue injury. In fact, a unique population of collagen-expressing cells derived from hematopoietic precursors termed “fibrocytes” has been described (9, 10) and is likely the bone marrow cell population from which the GFP-positive cells in the lungs of bleomycin-treated mice originate. Moreover, fibrocytes express the chemokine receptors CXCR4 and CCR7 and migrate in vitro in response to their corresponding ligands, stromal cell–derived factor-1 (SDF-1) and secondary lymphoid-tissue chemokine (SLC) (10). Hashimoto et al. demonstrated that levels of SDF-1 and SLC are increased in the lung following bleomycin treatment (5), indicating that these chemokines also may be the in vivo signals that recruit bone marrow–derived fibroblasts to the lung. In another study of radiation-induced fibrosis (11), influx of bone marrow–derived macrophages preceded that of bone marrow–derived fibroblasts, leading the authors to speculate that these macrophages may be the source of SDF-1, SLC, or other substances that recruit fibroblast precursors from the bone marrow.
Figure 2Bone marrow cell populations. (a) Cross section of tubular bone showing the structure of bone marrow. Hematopoietic spaces are organized into cords by stromal cells (green lines) and contain distinct foci of developing erythroid and granulocytic cells interspersed among immature hematopoietic precursors. Mature blood cells enter the circulation by migrating across the marrow sinus endothelium. (b) Two populations of stem cells may be isolated from bone marrow. Mesenchymal stem cells, isolated from marrow stroma, adhere to tissue culture plasticware and have been shown to have the potential to differentiate into osteoblasts, adipocytes, and chondrocytes. Hematopoietic stem cells, which do not adhere to tissue culture plasticware, not only have the capacity to produce mature blood cells but also have been shown to engraft into liver, lung, kidney, heart, skeletal muscle, pancreas, and gastrointestinal tract. Fibrocytes, defined by the cell surface expression of collagen I, CD11b, CD13, CD34, CD45RO, MHC class II, and CD86, express the same chemokine receptors, CXCR4 and CCR7, as the collagen I–positive, GFP-positive cells in bleomycin-induced fibrotic lesions.
Other investigators have systemically administered mesenchymal stem cells to bleomycin-treated mice (12, 13). In these studies, cells that engrafted into lung tissue displayed epithelial characteristics. The expression of epithelial markers by GFP-positive cells was not assessed by Hashimoto et al. (5), but it is intriguing to speculate that the GFP-positive, collagen-producing cells underwent epithelial-mesenchymal transition (14). Alternatively, the isolation and culture of bone marrow cells prior to reconstitution may have predisposed them to an epithelial phenotype. In any event, understanding mechanisms of engraftment will be important as clinical applications of bone marrow stem cell therapy are explored.
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