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Transplanted Mesenchymal Stem Cells Accelerate Glomerular Healing in Experimental Glomerulonephritis

Uta Kunter^*,, Song Rong^*,, Zivka Djuric^*, Peter Boor^*,, Gerhard Müller-Newen, Donghai Yu^* and Jürgen Floege^*

^* Division of Nephrology, Interdisciplinary Center for Clinical Research in Biomaterials and Tissue Material Interaction in Implants, and Institute of Biochemistry, University Hospital, Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany; and Department of Clinical and Experimental Pharmacotherapy, Slovak Medical University, Bratislava, Slovakia

Address correspondence to: Dr. Uta Kunter, Division of Nephrology, University Hospital RWTH Aachen, Pauwelsstrasse 30, D-52057 Aachen, Germany. Phone: +49-241-8089670; Fax: +49-241-8082446; E-mail: utakunter{at}gmx.de

Received for publication August 5, 2005. Accepted for publication May 10, 2006.

Bone marrow–derived cells contribute to glomerular cell turnover and repair, but the cell types involved are unknown. Whether rat mesenchymal stem cells (MSC) can accelerate recovery from damage in rat mesangioproliferative anti-Thy1.1 glomerulonephritis was studied. After injection into the left renal artery on day 2 after disease induction, fluorescently labeled MSC were detected in 20 to 50% of glomeruli and rare intrarenal vessels but not in the tubulointerstitium, in contralateral kidneys, or in medium controls. In control experiments, injected mesangial cells were detected less frequently in glomeruli in comparison with injected MSC. In nephritic outbred Wistar rats, MSC injection led to an approximately 50% reduction of mesangiolysis on days 4 and 6 after disease induction, accompanied by three- to four-fold higher intraglomerular cell proliferation on day 4 and more rapid mesangial reconstitution as detected by -smooth muscle actin expression. Injection of MSC into tail veins or intra-arterial injection of mesangial cells instead of MSC failed to reproduce any of these findings. In inbred Lewis rats, anti-Thy1.1 nephritis followed an aggravated course with transient acute renal failure. Acute renal failure was ameliorated by MSC injection into the left renal artery on day 2 after disease induction. Again, MSC led to more rapid recovery from mesangiolysis, increased glomerular cell proliferation, and reduction of proteinuria by 28%. Double immunostaining of 5-bromo-2'-deoxyuridine–labeled MSC for endothelial, mesangial, or monocyte/macrophage antigens showed that 85 to 95% of MSC that localized in glomeruli on day 6 failed to express these markers. In vitro, MSC secreted high amounts of vascular endothelial growth factor and TGF-1 but not PDGF-BB. In conclusion, even low numbers of MSC can markedly accelerate glomerular recovery from mesangiolytic damage possibly related to paracrine growth factor release and not to differentiation into resident glomerular cell types or monocytes/macrophages.

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