Fate Tracing Reveals the Pericyte and Not Epithelial Origin of Myofibroblasts in Kidney Fibrosis
01 Jan 2010-American Journal of Pathology (American Society for Investigative Pathology)-Vol. 176, Iss: 1, pp 85-97
TL;DR: Data indicate that therapeutic strategies directly targeting pericyte differentiation in vivo may productively impact fibrotic kidney disease.
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 β1 treatment. However, using either red fluorescent protein or β-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 β+, 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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TL;DR: The major components of this dynamic process, which involves hemodynamic alterations, inflammation, and endothelial and epithelial cell injury, followed by repair that can be adaptive and restore epithelial integrity or maladaptive, leading to chronic kidney disease are reviewed.
Abstract: Ischemic kidney injury often occurs in the context of multiple organ failure and sepsis. Here, we review the major components of this dynamic process, which involves hemodynamic alterations, inflammation, and endothelial and epithelial cell injury, followed by repair that can be adaptive and restore epithelial integrity or maladaptive, leading to chronic kidney disease. Better understanding of the cellular pathophysiological processes underlying kidney injury and repair will hopefully result in the design of more targeted therapies to prevent the injury, hasten repair, and minimize chronic progressive kidney disease.
1,579 citations
TL;DR: In ischemic, toxic and obstructive models of AKI, it is demonstrated that treatment with a JNK inhibitor, or bypassing the G2/M arrest by administration of a p53 inhibitor or the removal of the contralateral kidney, rescues fibrosis in the unilateral isChemic injured kidney.
Abstract: Fibrosis is responsible for chronic progressive kidney failure, which is present in a large number of adults in the developed world. It is increasingly appreciated that acute kidney injury (AKI), resulting in aberrant incomplete repair, is a major contributor to chronic fibrotic kidney disease. The mechanism that triggers the fibrogenic response after injury is not well understood. In ischemic, toxic and obstructive models of AKI, we demonstrate a causal association between epithelial cell cycle G2/M arrest and a fibrotic outcome. G2/M-arrested proximal tubular cells activate c-jun NH 2 -terminal kinase (JNK) signaling, which acts to upregulate profibrotic cytokine production. Treatment with a JNK inhibitor, or bypassing the G2/M arrest by administration of a p53 inhibitor or the removal of the contralateral kidney, rescues fibrosis in the unilateral ischemic injured kidney. Hence, epithelial cell cycle arrest at G2/M and its subsequent downstream signaling are hitherto unrecognized therapeutic targets for the prevention of fibrosis and interruption of the accelerated progression of kidney disease.
1,052 citations
TL;DR: The current understanding of the cellular and molecular mechanisms of renal fibrosis is outlined, which could offer novel insights into the development of new therapeutic strategies.
Abstract: Renal fibrosis, particularly tubulointerstitial fibrosis, is the common final outcome of almost all progressive chronic kidney diseases. Renal fibrosis is also a reliable predictor of prognosis and a major determinant of renal insufficiency. Irrespective of the initial causes, renal fibrogenesis is a dynamic and converging process that consists of four overlapping phases: priming, activation, execution and progression. Nonresolving inflammation after a sustained injury sets up the fibrogenic stage (priming) and triggers the activation and expansion of matrix-producing cells from multiple sources through diverse mechanisms, including activation of interstitial fibroblasts and pericytes, phenotypic conversion of tubular epithelial and endothelial cells and recruitment of circulating fibrocytes. Upon activation, matrix-producing cells assemble a multicomponent, integrin-associated protein complex that integrates input from various fibrogenic signals and orchestrates the production of matrix components and their extracellular assembly. Multiple cellular and molecular events, such as tubular atrophy, microvascular rarefaction and tissue hypoxia, promote scar formation and ensure a vicious progression to end-stage kidney failure. This Review outlines our current understanding of the cellular and molecular mechanisms of renal fibrosis, which could offer novel insights into the development of new therapeutic strategies.
1,052 citations
Cites background from "Fate Tracing Reveals the Pericyte a..."
...Studies suggest that vascular pericytes are a major source of myofibroblasts in fibrotic kidneys...
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TL;DR: The origin and the specific features of the myofibroblast in diverse fibrotic lesions, such as systemic sclerosis; kidney, liver, and lung fibrosis; and the stromal reaction to certain epithelial tumors are reviewed.
Abstract: The discovery of the myofibroblast has opened new perspectives for the comprehension of the biological mechanisms involved in wound healing and fibrotic diseases. In recent years, many advances have been made in understanding important aspects of myofibroblast basic biological characteristics. This review summarizes such advances in several fields, such as the following: i) force production by the myofibroblast and mechanisms of connective tissue remodeling; ii) factors controlling the expression of α-smooth muscle actin, the most used marker of myofibroblastic phenotype and, more important, involved in force generation by the myofibroblast; and iii) factors affecting genesis of the myofibroblast and its differentiation from precursor cells, in particular epigenetic factors, such as DNA methylation, microRNAs, and histone modification. We also review the origin and the specific features of the myofibroblast in diverse fibrotic lesions, such as systemic sclerosis; kidney, liver, and lung fibrosis; and the stromal reaction to certain epithelial tumors. Finally, we summarize the emerging strategies for influencing myofibroblast behavior in vitro and in vivo, with the ultimate goal of an effective therapeutic approach for myofibroblast-dependent diseases.
1,041 citations
Cites background from "Fate Tracing Reveals the Pericyte a..."
...Other interesting approaches are based on the possibility of terminating myofibroblast persistence by inducing their apoptosis(164) or their reversion to nonfibrogenic cell phenotypes.(108) In the case of the former, the ability of nitric oxide to induce myofibroblast apoptosis(165) suggests a possible therapeutic approach, such as by the use of phosphodiesterase-5 inhibitors....
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TL;DR: The data suggest that targeting diverse pathways is required to substantially inhibit the composite accumulation of myofibroblasts in kidney fibrosis, and specific deletion of Tgfbr2 in α-smooth muscle actin (αSMA)+ cells revealed the importance of this pathway in the recruitment of my ofibro Blasts through differentiation.
Abstract: Myofibroblasts are associated with organ fibrosis, but their precise origin and functional role remain unknown. We used multiple genetically engineered mice to track, fate map and ablate cells to determine the source and function of myofibroblasts in kidney fibrosis. Through this comprehensive analysis, we identified that the total pool of myofibroblasts is split, with 50% arising from local resident fibroblasts through proliferation. The nonproliferating myofibroblasts derive through differentiation from bone marrow (35%), the endothelial-to-mesenchymal transition program (10%) and the epithelial-to-mesenchymal transition program (5%). Specific deletion of Tgfbr2 in α-smooth muscle actin (αSMA)(+) cells revealed the importance of this pathway in the recruitment of myofibroblasts through differentiation. Using genetic mouse models and a fate-mapping strategy, we determined that vascular pericytes probably do not contribute to the emergence of myofibroblasts or fibrosis. Our data suggest that targeting diverse pathways is required to substantially inhibit the composite accumulation of myofibroblasts in kidney fibrosis.
1,041 citations
References
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TL;DR: A mechanistic link between Twist, EMT, and tumor metastasis is established, suggesting that Twist contributes to metastasis by promoting an epithelial-mesenchymal transition (EMT).
3,670 citations
TL;DR: Blood vessel walls harbor a reserve of progenitor cells that may be integral to the origin of the elusive MSCs and other related adult stem cells.
3,638 citations
TL;DR: This review highlights recent advances in the process of EMT signaling in health and disease and how it may be attenuated or reversed by selective cytokines and growth factors.
Abstract: Epithelial to mesenchymal transition (EMT) is a central mechanism for diversifying the cells found in complex tissues. This dynamic process helps organize the formation of the body plan, and while EMT is well studied in the context of embryonic development, it also plays a role in the genesis of fibroblasts during organ fibrosis in adult tissues. Emerging evidence from studies of renal fibrosis suggests that more than a third of all disease-related fibroblasts originate from tubular epithelia at the site of injury. This review highlights recent advances in the process of EMT signaling in health and disease and how it may be attenuated or reversed by selective cytokines and growth factors.
2,426 citations
TL;DR: Comparisons made between PDGF null mouse phenotypes suggest a general role for PDGFs in the development of myofibroblasts, and endothelial cells of the sprouting capillaries in the mutant mice appeared to be unable to attract PDGF-Rbeta-positive pericyte progenitor cells.
Abstract: Platelet-derived growth factor (PDGF)-B-deficient mouse embryos were found to lack microvascular pericytes, which normally form part of the capillary wall, and they developed numerous capillary microaneurysms that ruptured at late gestation. Endothelial cells of the sprouting capillaries in the mutant mice appeared to be unable to attract PDGF-Rbeta-positive pericyte progenitor cells. Pericytes may contribute to the mechanical stability of the capillary wall. Comparisons made between PDGF null mouse phenotypes suggest a general role for PDGFs in the development of myofibroblasts.
2,127 citations
TL;DR: The findings suggest that a substantial number of organ fibroblasts appear through a novel reversal in the direction of epithelial cell fate, which highlights the potential plasticity of differentiated cells in adult tissues under pathologic conditions.
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
1,929 citations