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Speaker: Christof Westenfelder, M.D.
Chief, Section of Nephrology
VA Medical Center
Professor of Medicine and Physiology (adjct.)
University of Utah
Salt Lake City, Utah
website: http://www.int.med.utah.edu/neph/bio.cfm?FacultyGUID=B36B0DAD4E9242DC89FB9B82FA5BF10A |
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Topic:
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"Use of Mesenchymal Stem Cells for the Treatment of Acute Kidney Injury: Mediator Mechanisms" |
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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 (2 x 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 proin-flammatory cytokines IL-1ß, TNF-ß, IFN-?, and inducible nitric oxide synthase was significantly reduced and that of anti-inflammatory IL-10 and bFGF, TGF-ß, 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.
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When:
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Monday, October 9, 2006
12:00PM – 1:00PM
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Location:
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Baldwin Auditorium
Robert H. Lurie Medical Research Center
303 East Superior Street, 1st floor |
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Selected Recent References for Christof Westenfelder, M.D.
Ittrich H, Lange C, Toegel F, Zander AR, Westenfelder C, Adam G, Nolte-Ernsting C. In vivo Magnetic Resonance Imaging of iron labeled, arterially injected Mesenchymal Stem Cells in Kidneys of Rats with ischemic Acute Kidney Injury. Exp Radiology (in press).
Bellamkonda K. Kishore, Jorge Isaac, and Christof Westenfelder. Administration of Poly-D-Glutamic Acid Induces the Proliferation of Erythropoietin-producing Peritubular Cells in Rat Kidney. Am J Physiol.
Kalani L. Raphael, LeAnne Swenson, and Christof Westenfelder.. Tretement of cancer associated anemia with erythropoietin has potential to promote progression of erythropoietin receptor expressing malignancies. CJASN (in press)
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Westenfelder C, Yang Y, Hu Z, Hu P, Toegel F, Clayton F. Carbamylated erythropoietin, a non-hematopoietic erythropoietin derivative, significantly improves survival and recovery from ischemic acute renal failure in rats with underlying chronic renal insufficency. Proc National Acad Sci USA 2006 (in print).
Coleman T, Westenfelder C, Toegel F, Yang Y, Hu Z, Leuvenink H, Katusic Z, D’Uscio L, Ghezzi P, Kaushansky K, Fox NE, Cerami A, Brines M. Erythropoietin heteroreceptors mediate distinctly different biological responses. Proc National Acad Sci USA 2006 (in print)
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Toegel F, Hu Z, Weiss K, Isaac J, Lange C, Westenfelder C. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol. 2005 Jul;289(1):F31-42. Epub 2005 Feb 15.
Toegel F, Isaac J, Hu Z, Weiss K, Westenfelder C. Renal SDF-1 Signals Mobilization and Homing of CXCR4-positive Cells to the Kidney after ischemic Injury. Kidney Int. 2005 May;67(5):1772-84.
Lange C, Tögel FE, Ittrich H, Clayton F, Nolte-Ernsting C, Zander AR, Westenfelder C: Administered Mesenchymal Stem Cells enhance recovery from ischemia/reperfusion-induced acute renal failure in rats. Kidney Int 68:1613-1617, 2005.
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