Evidence that fibroblasts derive from epithelium during tissue fibrosis
Abstract
Interstitial fibroblasts are principal effector cells of organ fibrosis in kidneys, lungs, and liver. While some view fibroblasts in adult tissues as nothing more than primitive mesenchymal cells surviving embryologic development, they differ from mesenchymal cells in their unique expression of fibroblast-specific protein-1 (FSP1). This difference raises questions about their origin. Using bone marrow chimeras and transgenic reporter mice, we show here that interstitial kidney fibroblasts derive from two sources. A small number of FSP1, CD34 fibroblasts migrate to normal interstitial spaces from bone marrow. More surprisingly, however, FSP1 fibroblasts also arise in large numbers by local epithelial-mesenchymal transition (EMT) during renal fibrogenesis. Both populations of fibroblasts express collagen type I and expand by cell division during tissue fibrosis. Our findings suggest that a substantial number of organ fibroblasts appear through a novel reversal in the direction of epithelial cell fate. As a general mechanism, this change in fate highlights the potential plasticity of differentiated cells in adult tissues under pathologic conditions.
Acknowledgments
We thank Brigid Hogan and Harold Moses at Vanderbilt University for helpful comments during the early preparation of this manuscript. Part of this work was presented in abstract form at the annual Meeting of the American Society of Nephrology in October, 2000. E.G. Neilson is supported in part by NIH grants DK-46282 and HL-68121.
Footnotes
See the related Commentary beginning on page 305.
Masayuki Iwano and David Plieth contributed equally to this work.
Conflict of interest: No conflict of interest has been declared.
Nonstandard abbreviations used: marrow stromal cells (MSCs); epithelial-mesenchymal transition (EMT); fibroblast-specific protein-1 (FSP1); green fluorescent protein (GFP); unilateral ureteral obstruction (UUO); bone marrow lining cell (BMLC).
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