Evidence that fibroblasts derive from epithelium during tissue fibrosis

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.

Intrarenal cells, not bone marrow–derived cells, are the major source for regeneration in postischemic kidney

“…This is in agreement with the report by Iwano et al that BMCs can differentiate into renal interstitial fibroblast (22). Renal IRI is accompanied by inflammatory cell infiltration, and the inflammation subsides after 10 days (42).…”

“…There is increasing evidence that circulating stem cells can enter the kidney and differentiate into renal cells after various injuries. We and others have shown that bone marrow cells (BMCs) can differentiate into tubular epithelial cells, glomerular endothelial cells, podocytes, mesangial cells, and renal interstitial cells (16)(17)(18)(19)(20)(21)(22). After transplanting hematopoietic stem cells isolated from male Rosa26 mice, we detected cells expressing β-gal in the renal tubules in female wild-type mice that had renal IRI.…”

The renal papilla is a niche for adult kidney stem cells

“…Indeed, adult neuronal stem cells display morphological and molecular characteristics of differentiated astrocytes (25). In addition, de-differentiation of renal epithelial cells into myofibroblasts, a long-suspected process (26), has recently been demonstrated conclusively (27), and it may be postulated that, as during limb and tail repair in some amphibians (28), de-differentiation of renal epithelial cells after organ injury may be followed by cell proliferation and re-differentiation into multiple cell types (29). Thus, terminally differentiated kidney cells may well be functioning as pluripotent stem cells during organ maintenance and repair.…”

“…Another potential origin for new, terminally differentiated kidney cells during kidney repair may be the mesenchymal cells that develop during the epithelial to mesenchymal transition, which occurs during renal injury (27), as found in other systems (28). A surprising recent finding has been the discovery that some of the new renal cells are derived from extrarenal cells.…”

Influence of ginsenoside Rg1, a panaxatriol saponin from Panax notoginseng, on renal fibrosis in rats with unilateral ureteral obstruction

“…Iwano et al(2002) found that a large proportion of interstitial fibroblasts were actually originated from local TEMT during renal fibrogenesis. In the process of TEMT, tubular epithelial cells lose epithelial cell marker E-cadherin and de novo express myofibroblast cell marker α-SMA (Liu, 2004).…”