Mesenchymal Stem Cells Prevent Progressive Experimental Renal Failure but Maldifferentiate into Glomerular Adipocytes

Abstract

Glomerulonephritis (GN) isM esenchymal stem cells (MSC) hold special promise for renal repair, because nephrons are largely of mesenchymal origin (1). The potential of MSC for renal repair has been shown in rodent models of acute renal failure (ARF), where the course of glycerol, cisplatin, or ischemia-reperfusion induced ARF was improved by MSC injection shortly after disease induction (2-5). In addition, we recently reported that injection of rat MSC into a renal artery can accelerate recovery from mesangiolytic damage and prevent transient ARF in rat anti-Thy1.1 glomerulonephritis (GN) (6). AntiThy1.1 nephritis is a model of acute mesangioproliferative glomerulonephritis and is characterized by initial mesangiolysis followed within a few days by glomerular repair via endothelial and mesangial cell proliferation and accumulation of mesangial matrix. We have also provided evidence that MSC likely exerted these effects in glomeruli by paracrine effects, such as the release of high amounts of vascular endothelial growth factor (VEGF) and TGF-␤1 rather than by differentiation into resident glomerular cell types or monocytes/macrophages (6).In this study, we investigated the long-term effects of MSC administration in early anti-Thy1.1 nephritis. Normally, antiThy1.1 nephritis in rats follows a self-limited course, and spontaneous restitution of the glomerular architecture can be observed within approximately 4 wk. For enhancement of the relevance of the model for progressive renal disease in humans, the model in this study was aggravated and transformed into a course of progressive renal failure by previous uninephrectomy of the rats (7,8). Materials and MethodsRats were housed under standard conditions in a light-, temperature-, and humidity-controlled environment with free access to tap water and standard rat diet. All animal protocols were approved by the local government authorities. Harvest and Culture of MSCInbred male Lewis rats that weighed 180 to 210 g (Harlan, Horst, Netherlands) served as bone marrow donors; MSC were prepared as described previously (6). Cells were seeded onto six-well plates (nine

Regeneration of Glomerular Podocytes by Human Renal Progenitors

“…Indeed, several studies have examined the possibility that bone-marrow-derived stem cells might be used for renal repair. [32][33][34][35][36] However, their beneficial role can be offset by their abnormal local differentiation into adipocytes accompanied by glomerular sclerosis. 33 In conclusion, the results of this study provide the first demonstration that glomerular injury can be repaired by using resident renal progenitor cells and suggest that the kidney might contain a "renopoietic system" ( Figure 6) with a bipotent progenitor localized at the urinary pole of Bowman's capsule, where it can initiate the replacement and regeneration of glomerular and tubular epithelial cells.…”

The role of microvesicles in tissue repair

“…In addition, evidence from murine studies has indicated that MSCs could maldifferentiate in glomerular adipocytes once injected in a rat model of progressive glomerulonephritis. 39 One possible alternative to the MSC infusion in organ transplantation might be MV treatment. One advantage of using MVs rather than the MSCs themselves is to avoid possible long-term maldifferentiation of engrafted cells or tumor generation.…”

Stem cell options for kidney disease

“…Some studies have shown improvement after MSC delivery in a model of glomerulonephropathy [54] and no evidence of a long-term fibrotic response 3 months after delivery of MSCs to animals with severe AKI [44]. Other studies have suggested that the beneficial effects linked to MSC injection can be marred by a long-term partial maldifferentiation of intraglomerular MSCs into adipocytes accompanied by glomerular sclerosis in a model of chronic glomerulonephritis [55]. Other studies have shown that in models of glomerular injury MSCs have no beneficial effect.…”