title: Human Wharton's jelly-derived mesenchymal stromal cells reduce renal fibrosis through induction of native and foreign hepatocyte growth factor synthesis in injured tubular epithelial cells.
abstract: BACKGROUND
  Based on some well-documented reports, we attempted to clarify the antifibrotic mechanisms of human Wharton's-jelly-derived mesenchymal stromal cells (WJ-MSCs) from the perspective of induction of hepatocyte growth factor (HGF) expression in tubular epithelial cells (TECs).
  
  
  METHODS
  A rat model of acute kidney injury (AKI) was established through unilateral renal ischemia for 1 hour. Two days later, a single intravenous cell or vehicle injection, or contralateral nephrectomy, was performed. Rats were sacrificed at 1 day, 1 week, 4 weeks, or 6 weeks after the intervention. Renal fibrosis was evaluated by Masson trichrome staining and Sircol collagen assay. The upregulation of α-smooth muscle actin (α-SMA) versus E-cadherin expression was adopted as an indicator of tubular epithelial-mesenchymal transition (EMT). Gene and protein expression of HGF or transforming growth factor-beta1 (TGF-β1) was determined by real-time polymerase chain reaction (RT-PCR) and Western blot, respectively. HGF expression in TECs was detected with immunostaining. In vitro, rat TECs subjected to hypoxia injury were incubated with or without conditioned medium (CM) from WJ-MSCs for 1, 3, 24, or 48 hours. Rat or human HGF synthesis in TECs was assessed with immunostaining, RT-PCR, or ELISA.
  
  
  RESULTS
  Cell delivery or nephrectomy led to abrogation of renal scarring. At the incipient period of AKI, through induction of HGF expression, either of them remarkably promoted the upregulation of HGF versus TGF-β1 expression in damaged kidney. Rat TECs were not only the principal cells expressing HGF but also exhibited human HGF expression after cell infusion. During fibrogenesis, the downregulation of HGF versus TGF-β1 expression was greatly prevented by WJ-MSCs or kidney removal, thereby resulting in tubular EMT delay. In vitro, after 24 or 48 hours of incubation, CM not only robustly induced the upregulation of rat HGF gene expression in TECs but substantially amplified the release of rat HGF. Under the induction of CM, human HGF mRNA and protein were detected in rat TECs.
  
  
  CONCLUSIONS
  WJ-MSCs contribute to tubular EMT delay and the alleviation of renal fibrosis. Induction of native and foreign HGF synthesis in damaged TECs at the initial stage of AKI leads to recovery of the disturbed balance of HGF/TGF-β1 during scar formation, being one of the vital mechanisms.
authors.forename: Tao
authors.initials: T
authors.lastname: Du
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Zou
authors.forename: Jun
authors.initials: J
authors.lastname: Cheng
authors.forename: Shuai
authors.initials: S
authors.lastname: Wu
authors.forename: Liang
authors.initials: L
authors.lastname: Zhong
authors.forename: Guanqun
authors.initials: G
authors.lastname: Ju
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
authors.forename: Guohua
authors.initials: G
authors.lastname: Liu
authors.forename: Yingjian
authors.initials: Y
authors.lastname: Zhu
authors.forename: Shujie
authors.initials: S
authors.lastname: Xia
mesh_terms: D000199:Actins / Q000378:metabolism; D058186:Acute Kidney Injury / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007684:Kidney Tubules / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D059631:Wharton Jelly / Q000166:cytology*
chemical_list: D000199:Actins; D015820:Cadherins; D017077:Culture Media, Conditioned; D017228:Hepatocyte Growth Factor; D053773:Transforming Growth Factor beta1; C498862:Acta2 protein, rat