title: Conditioned mesenchymal stem cells attenuate progression of chronic kidney disease through inhibition of epithelial-to-mesenchymal transition and immune modulation.
abstract: Mesenchymal stem cells (MSCs) have been shown to improve the outcome of acute renal injury models; but whether MSCs can delay renal failure in chronic kidney disease (CKD) remains unclear. In the present study, the were cultured in media containing various concentrations of basic fibroblast growth factor, epidermal growth factor and ascorbic acid 2-phosphate to investigate whether hepatocyte growth factor (HGF) secretion could be increased by the stimulation of these growth factors. Then, TGF-β1-treated renal interstitial fibroblast (NRK-49F), renal proximal tubular cells (NRK-52E) and podocytes were co-cultured with conditioned MSCs in the absence or presence of ascorbic acid 2-phosphate to quantify the protective effects of conditioned MSCs on renal cells. Moreover, male Sprague-Dawley rats were treated with 1 × 10(6) conditioned MSCs immediately after 5/6 nephrectomy and every other week through the tail vein for 14 weeks. It was found that basic fibroblast growth factor, epidermal growth factor and ascorbic acid 2-phosphate promoted HGF secretion in MSCs. Besides, conditioned MSCs were found to be protective against TGF-β1 induced epithelial-to-mesenchymal transition of NRK-52E and activation of NRK-49F cells. Furthermore, conditioned MSCs protected podocytes from TGF-β1-induced loss of synaptopodin, fibronectin induction, cell death and apoptosis. Rats transplanted with conditioned human MSCs had a significantly increase in creatinine clearance rate, decrease in glomerulosclerosis, interstitial fibrosis and increase in CD4(+)CD25(+)Foxp3(+) regulatory T cells counts in splenocytes. Together, our studies indicated that conditioned MSCs preserve renal function by their anti-fibrotic and anti-inflammatory effects. Transplantation of conditioned MSCs may be useful in treating CKD.
authors.affiliation: Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Jei-Wen
authors.initials: JW
authors.lastname: Chang
authors.forename: Hsin-Lin
authors.initials: HL
authors.lastname: Tsai
authors.forename: Chang-Wei
authors.initials: CW
authors.lastname: Chen
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Yang
authors.forename: An-Hang
authors.initials: AH
authors.lastname: Yang
authors.forename: Ling-Yu
authors.initials: LY
authors.lastname: Yang
authors.forename: Paulus S
authors.initials: PS
authors.lastname: Wang
authors.forename: Yee-Yung
authors.initials: YY
authors.lastname: Ng
authors.forename: Teng-Lung
authors.initials: TL
authors.lastname: Lin
authors.forename: Oscar K
authors.initials: OK
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis; D001205:Ascorbic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003404:Creatinine / Q000378:metabolism; D018450:Disease Progression; D004815:Epidermal Growth Factor / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005353:Fibronectins / Q000096:biosynthesis; D005355:Fibrosis; D005923:Glomerulosclerosis, Focal Segmental; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000166:cytology; D018655:Lymphocyte Count; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology*; D008840:Microfilament Proteins / Q000172:deficiency; D008875:Middle Aged; D009392:Nephrectomy; D050199:Podocytes / Q000166:cytology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D055815:Young Adult
chemical_list: D005353:Fibronectins; D008840:Microfilament Proteins; C503969:Synpo protein, rat; D053773:Transforming Growth Factor beta1; D016222:Fibroblast Growth Factor 2; C011669:ascorbate-2-phosphate; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D003404:Creatinine; D001205:Ascorbic Acid