Renal fibrosis and the origin of the renal fibroblast

Many studies have determined that the extent of tubulointerstitial involvement, particularly fibrosis, correlates better with renal function than glomerular changes do, thus, the extent of tubulointerstitial damage in any given renal biopsy has important implications for the renal prognosis of the patient (summarized in [1]). Tubulointerstitial fibrosis is characterized by the accumulation of extracellular matrix components including collagen types I, III, IV, proteoglycans and fibronectin. In recent years, much controversy has been created in the nephrology community regarding the origin of matrix-producing cells in the kidney. Several possibilities exist, including activation of resident interstitial fibroblasts, migrating haematopoietic or mesenchymal stem cells from the bone marrow, periadventitial cells and epithelial– mesenchymal transition (EMT) of tubular epithelial cells. This review summarizes recent data indicating the possible origin of matrix-producing cells in the kidney, and illustrates from a clinical point of view why this may be important. Traditionally, resident interstitial fibroblasts have been thought to be the sole source of extracellular matrix. In 1867, Cohnheim published a classical article on mechanisms of inflammation, stating that fibroblasts (called contractile cellular elements at that time) are descendents of migrating leucocytes [2]. This theory was widely believed for over a century, until Ross and coworkers [3] demonstrated, in a very elegant set of experiments with the use of parabiotic rats, that fibroblasts were of local origin. Nevertheless, recent studies point again to a possible bone marrow origin of at least some fibroblasts and the concept of fibroblast stem cells has gained wide popularity, though its exact contribution remains to be determined [4]. Moreover, periadventitial cells [5] and tubular epithelial cells [6] have been implicated as the origin of matrix-producing cells. Figure 1 summarizes the possible origins of cells synthesizing extracellular matrix within the tubulointerstitium.