Article

Fate Tracing Reveals the Pericyte and Not Epithelial Origin of Myofibroblasts in Kidney Fibrosis

Harvard University, Cambridge, Massachusetts, United States
American Journal Of Pathology (Impact Factor: 4.59). 12/2009; 176(1):85-97. DOI: 10.2353/ajpath.2010.090517
Source: PubMed

ABSTRACT

Understanding the origin of myofibroblasts in kidney is of great interest because these cells are responsible for scar formation in fibrotic kidney disease. Recent studies suggest epithelial cells are an important source of myofibroblasts through a process described as the epithelial-to-mesenchymal transition; however, confirmatory studies in vivo are lacking. To quantitatively assess the contribution of renal epithelial cells to myofibroblasts, we used Cre/Lox techniques to genetically label and fate map renal epithelia in models of kidney fibrosis. Genetically labeled primary proximal epithelial cells cultured in vitro from these mice readily induce markers of myofibroblasts after transforming growth factor beta(1) treatment. However, using either red fluorescent protein or beta-galactosidase as fate markers, we found no evidence that epithelial cells migrate outside of the tubular basement membrane and differentiate into interstitial myofibroblasts in vivo. Thus, although renal epithelial cells can acquire mesenchymal markers in vitro, they do not directly contribute to interstitial myofibroblast cells in vivo. Lineage analysis shows that during nephrogenesis, FoxD1-positive((+)) mesenchymal cells give rise to adult CD73(+), platelet derived growth factor receptor beta(+), smooth muscle actin-negative interstitial pericytes, and these FoxD1-derivative interstitial cells expand and differentiate into smooth muscle actin(+) myofibroblasts during fibrosis, accounting for a large majority of myofibroblasts. These data indicate that therapeutic strategies directly targeting pericyte differentiation in vivo may productively impact fibrotic kidney disease.

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Available from: Ben Humphreys, May 16, 2014
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    • "The second group of possible precursors of myofibroblasts are hepatocytes, cholangiocytes, and endothelial cells that can undergo epithelial or endothelial mesenchymal transition (EMT). However, several fate tracing and genetic labeling studies argued that hepatocytes or cholangiocytes did not undergo EMT in liver fibrosis models (Humphreys et al., 2010; Scholten et al., 2010; Taura et al., 2010). As for renal fibrosis, recent two studies argued that renal epithelial cells can undergo EMT, relaying signals to the interstitium to promote myofibroblast differentiation and fibrogenesis rather than directly giving rise to myofibroblasts population (Grande et al., 2015; Lovisa et al., 2015). "
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    • "Loss of stromal miRNAs results in a multifaceted renal phenotype The FoxD1-positive cortical renal stroma in the developing kidney marks a stromal progenitor population that gives rise to diverse cell lineages, including the cortical and medullary interstitial cells, glomerular mesangial cells, and pericytes (Kobayashi et al. 2014). To delineate the role of stromal miRNAs in renal development, we ablated Dicer, an endoribonuclease required for miRNA biogenesis , in the renal stroma and its derivatives by generating FoxD1 GC ;Dicer fl/fl transgenic mice (Harfe et al. 2005; Humphreys et al. 2010). To evaluate the excision of Dicer exon 24 from the Dicer fl allele by the FoxD1 GC allele, we performed quantitative real-time PCR and observed a significant decrease in exon 24 (***P < 0.001) but not exons 21 and 23 transcripts in our mutant model (Fig. 1A). "
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