Paracrine and differentiation mechanisms underlying stem cell therapy for the damaged kidney

Abstract

NATIVE KIDNEY ACUTE RENAL FAILURE (ARF) occurs in 2‐5% of hospitalized patients and is associated with high mortality (11). Allograft ARF occurs in 30‐50% of deceased donor kidney transplants and leads to longer hospital stays, a higher incidence of acute rejection, and reduced long-term graft survival (13). There is no specific therapy for ARF except for supportive care. A surge of evidence over the last decade supports an important role for inflammatory mediators, microvascular dysfunction, and apoptosis in the pathogenesis of the injury and extension phase of ARF (12). The mechanisms of recovery, less well understood, are felt to include a recapitulation of mechanisms originally involved in renal development. It is commonly believed that kidney progenitor cells, from either the kidney or an extrarenal source, repopulate the kidney during the recovery phase of ARF and drive the repair process (9). A popular model was that damaged/dead cells are removed and the kidney stem cells migrate to necrotic areas, differentiate, and repopulate the kidney. Indeed, injured human kidney transplants from female donors into male recipients were found to have Y chromosome staining of tubular epithelial cells, demonstrating that they were of recipient origin (5). In support of this model are studies in mice in which labeled bone marrow was tracked with -galactosidase (-gal) staining into postischemic kidney. -Gal staining was observed in 20% of the proximal tubular cells at 1 wk after ischemia, and also to some extent within 48 h of ischemia (7). Despite the focus on stem cell effects on repair, mice without functional bone marrow in that study had a worse early course of ARF, suggesting that bone marrow-derived cells had an early protective effect on the injury process. In another murine study, male-derived cells were found in female mouse kidney recipients after ischemia (8). However, recent work has shown that -gal staining to identify differentiated stem cells has considerable limitations, false positive results can result from the kidney’s endogenous -gal, and the staining validity is vulnerable to slight pH shifts (3). In a cisplatin model of ARF, administration of mesenchymal stem cells improved kidney function and structure (10). Given that Y chromosome-containing cells were found in recipient tubular epithelium of female mice and expressed specific lectin-binding proteins found in proximal tubules, transdifferentiation was concluded to be the mechanism of enhanced repair. Administration of skeletal muscle-derived stem cells that were differentiated into endothelial cells provided early protection from ischemic ARF in mice and were detected in glomeruli and peritubular capillaries using green fluorescent protein detection (1).