Resident mesenchymal cells and fibrosis.

Fibrosis is a major clinical problem associated with as many as 45% of all natural deaths in developed nations. It can affect all organs and accumulating evidence indicates that fibrogenesis is not merely a bystander product of injury, but is a central pathological problem directly contributing to loss of organ function. In the majority of clinical cases, fibrogenesis is strongly associated with the recruitment of leukocytes, even in the absence of infection. Although chronic infections are a significant cause of fibrogenesis, in most cases fibrotic disease occurs in the context of sterile injury, such as microvascular disease, toxic epithelial injury or diabetes mellitus. Fibrogenesis is a direct consequence of the activation of extensive, and previously poorly appreciated, populations of mesenchymal cells in our organs which are either wrapped around capillaries and known as 'pericytes', or embedded in interstitial spaces between cell structures and known as resident 'fibroblasts'. Recent fate-mapping and complementary studies in several organs indicate that these cells are the precursors of the scar-forming myofibroblasts that appear in our organs in response to injury. Here we will review the literature supporting a central role for these cells in fibrogenesis, and highlight some of the critical cell to cell interactions that are necessary for the initiation and continuation of the fibrogenic process. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.

Rho isoforms have distinct and specific functions in the process of epithelial to mesenchymal transition in renal proximal tubular cells.

Epithelial to mesenchymal transition (EMT) is involved in embryological development, cancerous metastatic spread and organ fibrosis, including the kidney. This process is largely driven by transforming growth factor-beta and recent evidence has implicated Rho as a key intracellular signalling molecule. In this study we have used RNA interference to silence the genetically distinct Rho (A, B and C) isoforms to define their individual functions in human kidney epithelial cells undergoing EMT. We demonstrate that the downregulation of the epithelial cell marker E-cadherin is dependent upon the Rho effector, Rho-kinase. However, silencing RhoA or RhoC expression also results in E-cadherin loss, though each by different mechanisms. Loss of RhoA leads to an upregulation of Snail1 and a reduction in the transcription of E-cadherin whereas loss of RhoC upregulates its breakdown via proteasomal degradation. During EMT, the upregulation of alpha-smooth muscle actin can be blocked by inhibiting the expression of RhoA, but not by that of RhoB or RhoC. This effect is independent of Rho-kinase activity. RhoC is the isoform solely responsible for stress fibre formation and inhibiting its expression reduces EMT-induced migration by 50%. RhoB appears to play a role in cell survival as inhibiting its expression leads to >300% increase in cell apoptosis and a relocalization of focal adhesion kinase. We conclude that Rho is a key signalling molecule in the process of EMT but that each isoform has a distinct and specific role.