The extrapulmonary origin of fibroblasts: stem/progenitor cells and beyond

Although intrapulmonary progenitor cells are traditionally believed to be the source for regenerating cells in response to lung injury, recent mounting evidence indicates that a significant proportion of the mesenchymal cells involved in this repair/remodeling process may be derived from extrapulmonary sources, such as the recently described circulating fibrocyte as well as other bone marrow-derived progenitor cells. Studies tracking CD34 and/or CD45 markers of fibrocytes show their presence in injured murine lung tissue. Moreover, bone marrow chimeric mice with green fluorescence protein (GFP)-expressing marrow cells show abundant GFP-expressing fibroblasts in their lungs in response to lung injury. However, although fibrocytes express CD34 and CD45, and appear to have the capacity to differentiate to myofibroblasts, these properties are not evident in the bone marrow-derived fibroblasts. Induction of CCL21 (SLC) and CXCR12 (SDF1alpha) in injured lung tissue, and their respective cognate receptors, CCR7 and CXCR4, in fibroblasts from injured lungs, suggests recruitment of these extrapulmonary progenitor cells via these chemokines. This is supported by evidence that antibody neutralization of CXCR12 reduces recruitment of fibrocytes and pulmonary fibrosis. In contrast, other studies suggest a protective effect for bone marrow-derived cells. Thus, although suggesting that influx of extrapulmonary fibroblast progenitor cells occurs in response to lung injury, these recent studies do not yet provide clear insight as to the actual phenotype and fate of the recruited cells, the identity of the progenitor cell population in bone marrow, and most important, the function or role of these cells in pathogenesis of the idiopathic interstitial pneumonias.