title: Bone marrow-derived cells contribute to podocyte regeneration and amelioration of renal disease in a mouse model of Alport syndrome.
abstract: In a model of autosomally recessive Alport syndrome, mice that lack the alpha3 chain of collagen IV (Col4alpha3(-/-)) 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 Col4alpha3. Female C57BL/6 Col4alpha3(-/-) (-/-) 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 alpha3(IV) protein by immunofluorescence. alpha3(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 Col4alpha3(-/-) 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.
authors.affiliation: Renal Section, Division of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, W12 0NN, London, United Kingdom. evangelia.prodromidi@imperial.ac.uk
authors.forename: Evangelia I
authors.initials: EI
authors.lastname: Prodromidi
authors.forename: Richard
authors.initials: R
authors.lastname: Poulsom
authors.forename: Rosemary
authors.initials: R
authors.lastname: Jeffery
authors.forename: Candice A
authors.initials: CA
authors.lastname: Roufosse
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Pollard
authors.forename: Charles D
authors.initials: CD
authors.lastname: Pusey
authors.forename: H Terence
authors.initials: HT
authors.lastname: Cook
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000378:metabolism; D001854:Bone Marrow Cells; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D049109:Cell Proliferation; D024141:Collagen Type IV / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005455:Fluorescent Antibody Technique; D050533:Glomerular Basement Membrane / Q000378:metabolism / Q000473:pathology; D017403:In Situ Hybridization; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009394:Nephritis, Hereditary / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D050199:Podocytes / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012038:Regeneration; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001324:Autoantigens; D024141:Collagen Type IV; D012333:RNA, Messenger; C057112:type IV collagen alpha3 chain