Severe acute renal failure (ARF) remains a common, largely treatment-resistant clinical problem with disturbingly high mortality rates. Therefore, we tested whether administration of multipotent mesenchymal stem cells (MSC) to anesthetized rats with ischemia-reperfusion-induced ARF (40-min bilateral renal pedicle clamping) could improve the outcome through amelioration of inflammatory, vascular, and apoptotic/necrotic manifestations of ischemic kidney injury. Accordingly, intracarotid administration of MSC (∼ 106/animal) either immediately or 24 h after renal ischemia resulted in significantly improved renal function, higher proliferative and lower apoptotic indexes, as well as lower renal injury and unchanged leukocyte infiltration scores. Such renoprotection was not obtained with syngeneic fibroblasts. Using in vivo two-photon laser confocal microscopy, fluorescence-labeled MSC were detected early after injection in glomeruli, and low numbers attached at microvasculature sites. However, within 3 days of administration, none of the administered MSC had differentiated into a tubular or endothelial cell phenotype. At 24 h after injury, expression of proinflammatory cytokines IL-1β, TNF-α, IFN-γ, and inducible nitric oxide synthase was significantly reduced and that of anti-inflammatory IL-10 and bFGF, TGF-α, and Bcl-2 was highly upregulated in treated kidneys. We conclude that the early, highly significant renoprotection obtained with MSC is of considerable therapeutic promise for the cell-based management of clinical ARF. The beneficial effects of MSC are primarily mediated via complex paracrine actions and not by their differentiation into target cells, which, as such, appears to be a more protracted response that may become important in late-stage organ repair.

Acute kidney injury (AKI) is a major clinical problem in which a critical vascular, pathophysiological component is recognized. We demonstrated previously that mesenchymal stem cells (MSC), unlike fibroblasts, are significantly renoprotective after ischemia-reperfusion injury and concluded that this renoprotection is mediated primarily by paracrine mechanisms. In this study, we investigated whether MSC possess vasculoprotective activity that may contribute, at least in part, to an improved outcome after ischemia-reperfusion AKI. MSC-conditioned medium contains VEGF, HGF, and IGF-1 and augments aortic endothelial cell (EC) growth and survival, a response not observed with fibroblast-conditioned medium. MSC and EC share vasculotropic gene expression profiles, as both form capillary tubes in vitro on Matrigel alone or in cooperation without fusion. MSC undergo differentiation into an endothelial-like cell phenotype in culture and develop into vascular structures in vivo. Infused MSC were readily detected in the kidney early after reflow but were only rarely engrafted at 1 wk post-AKI. MSC attached in the renal microvascular circulation significantly decreased apoptosis of adjacent cells. Infusion of MSC immediately after reflow in severe ischemia-reperfusion AKI did not improve renal blood flow, renovascular resistance, or outer cortical blood flow. These data demonstrate that the unique vasculotropic, paracrine actions elicited by MSC play a significant renoprotective role after AKI, further demonstrating that cell therapy has promise as a novel intervention in AKI.

Our data show that renal SDF-1 is a currently unrecognized mediator of homing to and migration of CXCR4 expressing cells in the injured kidney. Because certain cells that express CXCR4 may have renoprotective effects, our results suggest that SDF-1 may be a major signal involved in kidney repair.

We conclude that the highly renoprotective capacity of mesenchymal stem cells opens the possibility for a cell-based paradigm shift in the treatment of I/R ARF.

Acute kidney injury (AKI) is a major clinical problem associated with high morbidity and mortality. Likely due to its complex pathophysiology, therapies with a single pharmacological agent have generally failed to improve outcomes. In contrast, stem cell-based interventions utilize these cells' ability to simultaneously target multiple pathophysiological components of AKI and thus represent a promising new tool for the treatment of AKI. The aims of the this study were to investigate the long-term outcome and safety of treatment with autologous and allogeneic mesenchymal stem cells (MSCs) after AKI and the role of vascular endothelial growth factor (VEGF) as one of the principal paracrine mediators of renoprotection of MSCs. MSC administration after AKI was not associated with adverse events and proved to be renoprotective in animals with severe renal failure. Identical doses of autologous MSC were more effective than allogeneic. At 3 months, MSCs were not engrafted in any tissues except in the bone marrow in 50% of animals given the highest allogeneic cell dose. There was no long-term fi brotic response in the kidneys attributable to MSC therapy, and animals with severe AKI were protected from development of fi brotic lesions after AKI. Furthermore, this study establishes VEGF as a critical factor mediating renal recovery. VEGF knockdown by small-interfering RNA reduced effectiveness of MSCs signifi cantly and decreased survival. In summary, our results show that both autologous and allogeneic MSC are safe and effective in AKI, and importantly, reduce late renal fi brosis and loss of renal function in surviving animals and that VEGF is a critical factor in renoprotection by MSCs. Together, we posit that these data provide further justifi cation for the conduct of clinical trails in which AKI is treated with MSC.