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


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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    ABSTRACT: Chronic liver injury, resulted from different etiologies (e.g. virus infection, alcohol abuse, nonalcoholic steatohepatitis (NASH) and cholestasis) can lead to liver fibrosis characterized by the excess accumulation of extracellular matrix (ECM) proteins (e.g. type I collagen). Hepatic myofibroblasts that are activated upon liver injury are the key producers of ECM proteins, contributing to both the initiation and progression of liver fibrosis. Hepatic stellate cells (HSCs) and to a lesser extent, portal fibroblast, are believed to be the precursor cells that give rise to hepatic myofibroblasts in response to liver injury. Although much progress has been made towards dissecting the lineage origin of myofibroblasts, how these cells are activated and become functional producers of ECM proteins remains incompletely understood. Activation of myofibroblasts is a complex process that involves the interactions between parenchymal and non-parenchymal cells, which drives the phenotypic change of HSCs from a quiescent stage to a myofibroblastic and active phenotype. Accumulating evidence has suggested a critical role of NADPH oxidase (NOX), a multi-component complex that catalyzes reactions from molecular oxygen to reactive oxygen species (ROS), in the activation process of hepatic myofibroblasts. NOX isoforms, including NOX1, NOX2 and NOX4, and NOX-derived ROS, have all been implicated to regulate HSC activation and hepatocyte apoptosis, both of which are essential steps for initiating liver fibrosis. This review highlights the importance of NOX isoforms in hepatic myofibroblast activation and the progression of liver fibrosis, and also discusses the therapeutic potential of targeting NOXs for liver fibrosis and associated hepatic diseases.
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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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    ABSTRACT: MicroRNAs are small noncoding RNAs that post-transcriptionally regulate mRNA levels. While previous studies have demonstrated that miRNAs are indispensable in the nephron progenitor and ureteric bud lineage, little is understood about stromal miRNAs during kidney development. The renal stroma (marked by expression of FoxD1) gives rise to the renal interstitium, a subset of peritubular capillaries, and multiple supportive vascular cell types including pericytes and the glomerular mesangium. In this study, we generated FoxD1(GC);Dicer(fl/fl) transgenic mice that lack miRNA biogenesis in the FoxD1 lineage. Loss of Dicer activity resulted in multifaceted renal anomalies including perturbed nephrogenesis, expansion of nephron progenitors, decreased renin-expressing cells, fewer smooth muscle afferent arterioles, and progressive mesangial cell loss in mature glomeruli. Although the initial lineage specification of FoxD1(+) stroma was not perturbed, both the glomerular mesangium and renal interstitium exhibited ectopic apoptosis, which was associated with increased expression of Bcl2l11 (Bim) and p53 effector genes (Bax, Trp53inp1, Jun, Cdkn1a, Mmp2, and Arid3a). Using a combination of high-throughput miRNA profiling of the FoxD1(+)-derived cells and mRNA profiling of differentially expressed transcripts in FoxD1(GC);Dicer(fl/fl) kidneys, at least 72 miRNA:mRNA target interactions were identified to be suppressive of the apoptotic program. Together, the results support an indispensable role for stromal miRNAs in the regulation of apoptosis during kidney development.
    Full-text · Article · Oct 2015
    • "The authors go on to show that the differentiation of pericytes into myofibroblasts is driven by SnaiI and Id1 transcripts (Lin et al., 2008). Further studies employing fate mapping in mouse models of UUO have established that pericytes, not ECs, undergo proliferative expansion and differentiate into myofibroblasts during UUO (Humphreys et al., 2010). Further analysis into Types 1 and 2 subpopulations of pericytes show that pericytes react differently to injury depending on the organ affected. "
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    ABSTRACT: Regenerative medicine using mesenchymal stem cells for the purposes of tissue repair has garnered considerable public attention due to the potential of returning tissues and organs to a normal, healthy state after injury or damage has occurred. To achieve this, progenitor cells such as pericytes and bone marrow-derived mesenchymal stem cells can be delivered exogenously, mobilised and recruited from within the body or transplanted in the form organs and tissues grown in the laboratory from stem cells. In this review, we summarise the recent evidence supporting the use of endogenously mobilised stem cell populations to enhance tissue repair along with the use of mesenchymal stem cells and pericytes in the development of engineered tissues. Finally, we conclude with an overview of currently available therapeutic options to manipulate endogenous stem cells to promote tissue repair. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Mar 2015 · Pharmacology [?] Therapeutics
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