Editors' ChoiceKidney Fibrosis

The Enemy Within

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Science Translational Medicine  24 Mar 2010:
Vol. 2, Issue 24, pp. 24ec49
DOI: 10.1126/scitranslmed.3001078

Epithelial cells and their underlying basement membrane serve as barriers that separate various lumina in the body from the surrounding stroma. Early in embryogenesis, the epithelial lining forms first, and then some epithelial cells cross the basement membrane and migrate inwards, forming collagen-secreting fibroblasts, which are the main cellular component of the stroma. This “epithelial-to-mesenchymal transition,” or EMT, has fascinated researchers for decades. A type of fibroblast—the myofibroblast—participates in wound healing, but when it is overactive the excessive matrix paralyzes an organ such as the liver or kidney in a process referred to as fibrosis. A provocative hypothesis has been proposed that, in kidney fibrosis, the myofibroblasts are derived from the epithelium of the renal tubules. Indeed, renal epithelial cells can be forced to undergo EMT in culture. But does this happen in the intact kidney?

To address this question, Humphreys and colleagues used a mouse model of kidney fibrosis. The gold standard for proving a cell’s origin is a technique known as lineage tracing, in which two lines of mice are crossed: One carries a marker gene such as green fluorescent protein or LacZ with an incapacitating “stop” sequence, and the other expresses Cre recombinase, which removes the stop sequence. The authors used mice expressing Cre in kidney epithelium–forming cells and thus generated mice in which the entire kidney epithelium was permanently marked. When they induced fibrosis in these mice, not a single myofibroblast was marker-positive. In contrast, when Cre was expressed in kidney stroma myofibroblasts were marker-positive. Thus, at least in the mouse model of kidney fibrosis EMT does not occur. Instead, the authors show that myofibroblasts are derived in part from microvascular pericytes, the cells forming the outer layer of capillary walls. Pericytes are fascinating cells that not only regulate blood vessel formation but have been recently shown to act as mesenchymal stem cells in various tissues.

This study brings us one step closer to understanding the mechanism of fibrosis and points to the pericyte as a major player in this process. The authors suggest that therapy aimed at preventing myofibroblast formation from pericytes can alleviate fibrosis. It remains to be seen whether myofibroblasts in other organs and pathological states such as cancer are of pericyte origin as well.

B. D. Humphreys et al., Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am. J. Pathol. 176, 85–97 (2010). [Abstract]

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