Bone marrow-derived cells contribute to podocyte regeneration and amelioration of renal disease in a mouse model of Alport syndrome

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, 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 reverse transcription-polymerase chain reaction 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 wildtype donors, and the mechanism by which this occurs may in part involve generation of podocytes without the gene defect.