Direct contribution of epithelium to organ fibrosis: epithelial-mesenchymal transition

Summary

Fibrosis of epithelial parenchymal organs and end-stage organ failure represent the final common pathway of many chronic diseases and are a major determinant of morbidity and mortality worldwide. Fibrosis is a complex response initiated to protect the host from an injurious event; nevertheless, it leads to serious organ damage when it becomes independent from the initiating stimulus. It involves massive deposition of matrix by an expanded pool of fibrogenic cells, disruption of the normal tissue architecture, and parenchymal destruction. Fibroblasts, the effector cells of matrix production, when engaged in fibrogenesis, display the highly activated phenotype characteristic of myofibroblasts. These cells are present in a large number in sites with ongoing inflammation, reparative reaction, and fibrosis, but their origin has not yet been definitely elucidated. Although proliferation of preexisting stromal fibroblasts and, probably, recruitment of bone marrow–derived fibrogenic cells may account for a portion of them, emerging evidence seems to indicate that an important number of matrix-producing fibroblasts/myofibroblasts arises through a mechanism of epithelial-mesenchymal transition. Through this process, epithelial cells would lose intercellular cohesion and would translocate from the epithelial compartment into the interstitium where, gaining a full mesenchymal phenotype, they could participate in the synthesis of the fibrotic matrix. Epithelial-mesenchymal transition is induced by the integrated actions of many stimuli including transforming growth factor-β and matrix-generated signals that are also known to be implicated in inflammation, repair responses, and fibrosis. The consequences of epithelial-mesenchymal transition in chronic fibrosing diseases could be two-fold as follows: on one hand, by supplementing new mesenchymal cells, it might feed the expanding pool of interstitial fibroblasts/myofibroblasts responsible for the matrix accumulation; on the other hand, it could cause loss of epithelial cells, thus, contributing to the parenchyma destruction seen in advanced fibrosis. Markers of epithelium undergoing epithelial-mesenchymal transition include loss of E-cadherin and cytokeratin; de novo expression of fibroblast-specific protein 1/S100A4, vimentin, and α-smooth muscle actin; basement membrane component loss; and production of interstitial-type matrix molecules such as fibronectin and type I/III collagen. Evidence of epithelial-mesenchymal transition has been reported in the kidney, lung, liver, eye, and serosal membranes suggesting that epithelial-mesenchymal transition could be involved in the pathogenesis of fibrotic disorders in these organs. Thus, because of its fibrogenic potential, the detection of epithelial-mesenchymal transition in biopsy specimens could be useful diagnostically and represent a new biomarker of progression in chronic fibrosing diseases.

Introduction

On the basis of their morphology and functional characteristics, traditional histology distinguishes two basic tissue organizations, epithelia and mesenchymal (connective) tissue, each of which is engaged in specific functions. Epithelia are multicellular structures composed of closely associated cells that adhere tightly to the underlying basement membrane and line cavities, serving as protective barriers and absorptive/secretory surfaces. Mesenchymal tissue consists of loosely organized cells living more individually within the extracellular matrix that they themselves produce, and they are endowed with considerable migratory capability [1]. The accomplishment of specialized functions by epithelial and mesenchymal tissues indicates on one hand a high degree of differentiation of their constituent cells and on the other hand suggests that they have to maintain stability in their differentiated state to serve these specific tasks [2]. Indeed, the alleged stability of differentiation underlies the commonly accepted belief that the phenotype of “terminally differentiated” adult tissues is immutable [2], [3]. However, it is increasingly appreciated that, also in highly specialized cells, the unexpressed genetic information is not permanently inactivated, thus, suggesting that the concept of a “terminally differentiated” tissue may be an oversimplification [3]. Until some years ago, it was conceptually difficult to envision that a highly differentiated tissue featuring a well-defined repertoire of specialized functions could change its genetic program and adopt another one. However, evidence is accumulating that epithelial cells can change their phenotype and acquire mesenchymal properties through a process known as epithelial-mesenchymal transition (EMT) through which they can increase their capability to move and/or to synthesize interstitial matrix. EMT is normally seen in tissue morphogenesis during embryonic development and, in addition, is involved in the progression of carcinoma where it facilitates the generation of migratory neoplastic cells at the tumor invasive front [1]. Furthermore, it is gaining growing acceptance that EMT may also participate in tissue repair and fibrosis after injury by conferring to epithelial cells a phenotype suitable for facing adverse environmental conditions and useful in repairing the injury-damaged tissue [1], [2].

In spite of the importance of fibrosis in progressive chronic diseases, only histologic criteria are currently used for its pathologic assessment, usually limited to the mere estimation of the amount of accumulated matrix, thus, implying the advisability of searching for new parameters yielding more diagnostic information [4]. Because matrix accumulation is associated with expansion of interstitial fibroblasts/myofibroblasts and because this step is crucial for the development of fibrosis [5], additional insights may be provided by studying the pathways involved in the formation of these cells. This article reviews the current knowledge of the role of EMT in the generation of fibroblasts/myofibroblasts in fibrosis, discusses the molecular mechanisms involved, and finally, highlights the possible occurrence of EMT in some human fibrotic disorders.