Transdifferentiation comes of age

Abstract

Five years ago we wrote an editorial in this journal expressing a-smooth-muscle actin can be detected even about the possible transdifferentiation of tubular epi- under physiological conditions in humans, as was thelial cells to fibroblasts [1]. We had just cloned a pointed out by Alpers and colleagues [7]. In addition, fibroblast specific protein ( FSP)-1 in murine kidney whereas in dermal myofibroblasts, desmin expression fibroblasts and had described that de novo expression has been described in some of these cells and has been of this protein could be detected in selected tubular used to classify them accordingly [8], no such expresepithelial cells during late stages of renal fibrogenesis, sion has been noted in kidney fibroblasts. Still, it seems indicating possible epithelial–mesenchymal trans- clear that not all interstitial fibroblasts convert into formation ( EMT ) or transdifferentiation [2]. After this myofibroblasts and it is highly likely that at least some passage of time, we would like to readdress the issue fibroblasts are not derived from resident interstitial of transdifferentiation and the scientific evidence col- fibroblasts, but also from tubular epithelial cells. lected in the meantime supporting its existence. As was pointed out in that first editorial, transdifferentiation is defined as the loss of one phenotype and the acquisition of a new one. Transdifferentiation is a In vivo evidence of tubular epithelial–mesenchymal physiological process during development but has also been described in a number of adult organs including transdifferentiation the liver, the thyroid and the mammary glands (reviewed in [3]). The kidney seems particularly well As stated above, the concept of renal transdifferentisuited for changes in phenotype since, with the excep- ation of tubular epithelial cells resulted from the de tion of collecting duct cells (which are derived from novo expression of an otherwise fibroblast-specific prothe ureteric epithelium), all kidney cells are derivatives tein in tubular epithelial cells during fibrogenesis in a of the metanephric mesenchyme. Recently, Ng and mouse model of anti-tubular basement membrane discolleagues [4] were able to demonstrate that glomerular ease. Similar observations were made in a model of epithelial cells may undergo transdifferentiation to anti-glomerular basement membrane disease and in a myofibroblasts. Regarding renal fibroblasts, trans- model of toxic nephropathy (unpublished observadifferentiation occurs regularly although it is usually tions). Nadasdy et al. had already described mesennot so termed. During fibrogenesis, resident interstitial chymally appearing cells within the interstitium of fibroblasts undergo a change of phenotype expressing human kidneys with marked fibrosis. These cells, new molecules such as a-smooth-muscle actin whose though of fibroblast appearance and localization, still expression is normally confined to vascular smooth- expressed several epithelial marker proteins, indicating muscle cells. Hence the new name ‘myofibroblasts’ for that they may represent transitional cells between these cells. The number of interstitial a-smooth-muscle epithelial and mesenchymal state [9]. These observaactin-positive cells correlated with the degree of fibrosis tions were corroborated in a well-performed study by and renal function in animal studies [5] and in human Ng and co-workers [10] in the rat model of 5/6 disease such as IgA nephropathy [6 ]. It is widely nephrectomy. Using immunohistochemistry and in-situ assumed that these activated ‘myofibroblasts’ prolifer- hybridizations, the group noted de novo expression of ate and synthesize the extracellular matrix substances the myofibroblast marker a-smooth-muscle actin in responsible for the widening of the tubulointerstitial some tubular epithelial cells [10]. By electron micro