title: Transplanted mesenchymal stem cells accelerate glomerular healing in experimental glomerulonephritis.
abstract: 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 alpha-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-beta1 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.
authors.affiliation: Division of Nephrology, University Hospital, Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany. utakunter@gmx.de
authors.forename: Uta
authors.initials: U
authors.lastname: Kunter
authors.forename: Song
authors.initials: S
authors.lastname: Rong
authors.forename: Zivka
authors.initials: Z
authors.lastname: Djuric
authors.forename: Peter
authors.initials: P
authors.lastname: Boor
authors.forename: Gerhard
authors.initials: G
authors.lastname: Müller-Newen
authors.forename: Donghai
authors.initials: D
authors.lastname: Yu
authors.forename: Jürgen
authors.initials: J
authors.lastname: Floege
mesh_terms: D000818:Animals; D021461:Animals, Outbred Strains; D000954:Antigens, Surface / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D005920:Glomerular Mesangium / Q000473:pathology / Q000503:physiopathology*; D005921:Glomerulonephritis / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy* / Q000652:urine; D007150:Immunohistochemistry; D007269:Injections, Intra-Arterial; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; D015415:Biomarkers; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A