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First published online July 27, 2006
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2006-0201v1
24/11/2448    most recent
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Submitted on April 9, 2006
Accepted on July 11, 2006

Tissue-Specific Stem Cells

Bone Marrow Derived-Cells Contribute to Podocyte Regeneration and Amelioration of Renal Disease in a Mouse Model of Alport Syndrome

Evangelia I. Prodromidi 1*, Richard Poulsom 2, Rosemary Jeffery 2, Candice A. Roufosse 3, Patrick J. Pollard 4, Charles D. Pusey 1, H. Terence Cook 3

1 Renal Section, Division of Medicine, Imperial College London, Hammersmith Campus, London, United Kingdom
2 Histopathology Unit, Cancer Research UK, London Research Institute, London, United Kingdom
3 Department of Histopathology, Division of Medicine, Imperial College London, Hammersmith Campus, London, United Kingdom
4 Molecular Population Genetics Laboratory, Cancer Research UK, London Research Institute, London, United Kingdom

* To whom correspondence should be addressed. E-mail: evangelia.prodromidi{at}imperial.ac.uk.


  Abstract

In a model of autosomally recessive Alport syndrome, mice that lack the {alpha}3 chain of collagen IV (Col4{alpha}3-/-), develop progressive glomerular damage leading to renal failure. The proposed mechanism is that podocytes fail to synthesize normal glomerular basement membrane (GBM), so the collagen IV network is unstable and easily degraded. We used this model to study whether bone marrow (BM) transplantation can rectify this podocyte defect by correcting the deficiency in Col4{alpha}3. Female C57BL/6 Col4{alpha}3-/- (-/-) mice were transplanted with whole BM from male wild type (+/+) mice. Control female -/- mice received BM from male -/- littermates. Serum urea and creatinine levels were significantly lower in recipients of +/+ BM compared with those of -/- BM 20 weeks post-transplant. Glomerular scarring and interstitial fibrosis were also significantly decreased. Donor-derived cells were detected by in situ hybridization (ISH) for the Y chromosome, and fluorescence and confocal microscopy indicated that some showed an apparent podocyte phenotype in mice transplanted with +/+ BM. Glomeruli of these mice showed small foci of staining for {alpha}3(IV) protein by immunofluorescence. {alpha}3(IV) mRNA was detectable by RT-PCR and ISH in some mice transplanted with +/+ BM but not -/- BM. However, a single injection of mesenchymal stem cells from +/+ mice to irradiated -/- recipients did not improve renal disease. Our data show that improved renal function in Col4{alpha}3-/- mice results from BM transplantation from wild type donors and the mechanism by which this occurs may in part involve generation of podocytes without the gene defect.




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