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Am J Physiol Renal Physiol (February 15, 2005). doi:10.1152/ajprenal.00007.2005
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Submitted on January 11, 2005
Accepted on February 8, 2005

Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms

Florian Togel1, Zhuma Hu2, Kathleen Weiss2, Jorge Isaac3, Claudia Lange4, and Christof Westenfelder1*

1 Department of Medicine, Division of Nephrology and VA Medical Center, University of Utah, Salt Lake City, UT, USA; Department of Physiology, University of Utah, Salt Lake City, UT, USA
2 Department of Medicine, Division of Nephrology and VA Medical Center, University of Utah, Salt Lake City, UT, USA
3 Department of Pathology, University of Utah, Salt Lake City, UT, USA
4 Bone Marrow Transplantation Center, University of Hamburg, Hamburg, Germany

* To whom correspondence should be addressed. E-mail: c.Westenfelder{at}uofu.net.

Severe acute renal failure (ARF) remains a common, largely treatment resistant clinical problem with disturbingly high mortality rates. We tested, therefore, whether administration of multipotent mesenchymal stem cells (MSC) to anesthetized rats with ischemia/reperfusion-induced (I/R) ARF (40 min bilateral renal pedicle clamping) could improve 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 hours after renal ischemia, resulted in significantly improved renal function, higher proliferative and lower apoptotic indices, 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 tubular or endothelial cell phenotype. At 24 hours after injury, expression of pro-inflammatory cytokines IL-1{beta}, TNF-{alpha} , IFN{gamma}, and iNOS was significantly reduced and that of anti-inflammatory IL-10, and bFGF, TGF-{alpha} and Bcl-2 was highly upregulated in treated kidneys. We conclude that the early and 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.




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