title: Mesenchymal stem cell-derived microparticles ameliorate peritubular capillary rarefaction via inhibition of endothelial-mesenchymal transition and decrease tubulointerstitial fibrosis in unilateral ureteral obstruction.
abstract: BACKGROUND
  Microparticles (MPs) derived from kidney-derived mesenchymal stem cells (KMSCs) have recently been reported to ameliorate rarefaction of peritubular capillaries (PTC) in ischemic kidneys via delivery of proangiogenic effectors. This study aimed to investigate whether KMSC-derived MPs show anti-fibrotic effects by ameliorating endothelial-to-mesenchymal transition (EndoMT) in human umbilical vein endothelial cells (HUVEC) in vitro and by preserving PTC in kidneys with unilateral ureteral obstruction (UUO) in vivo.
  
  
  METHODS
  MPs isolated from the supernatants of KMSC were co-cultured with HUVEC to assess their in vitro biologic effects on endothelial cells. Mice were treated with MPs via the tail vein after UUO injury to assess their anti-fibrotic and PTC sparing effects. Renal tubulointerstitial damage and inflammatory cell infiltration were examined with Masson's trichrome, F4/80 and α-smooth muscle actin (α-SMA) staining and PTC rarefaction index was determined by CD31 staining.
  
  
  RESULTS
  KMSC-derived MPs significantly ameliorated EndoMT and improved in vitro proliferation of TGF-β1 treated HUVEC. In vivo administration of KMSC-derived MPs significantly inhibited EndoMT of PTC endothelial cells and improved PTC rarefaction in UUO kidneys. Furthermore, administration of KMSC-derived MPs inhibited inflammatory cell infiltration as well as tubulointerstitial fibrosis in UUO mice as demonstrated by decreased F4/80 and α-SMA-positive cells and Masson's trichrome staining, respectively.
  
  
  CONCLUSIONS
  Our results suggest that KMSC-derived MPs ameliorate PTC rarefaction via inhibition of EndoMT and protect against progression of renal damage by inhibiting tubulointerstitial fibrosis.
authors.affiliation: Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. hychoi.dr@gmail.com.|Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul, Korea. hychoi.dr@gmail.com.
authors.forename: Hoon Young
authors.initials: HY
authors.lastname: Choi
authors.affiliation: Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, Korea. HLEE23@yuhs.ac.
authors.forename: Hyun Gyu
authors.initials: HG
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. docbsk@yuhs.ac.
authors.forename: Beom Seok
authors.initials: BS
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. dkwlxm@hanmail.net.
authors.forename: Sun Hee
authors.initials: SH
authors.lastname: Ahn
authors.affiliation: Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. eeyorelove@hanmail.net.
authors.forename: Ara
authors.initials: A
authors.lastname: Jung
authors.affiliation: Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. alfo0103@naver.com.
authors.forename: Mirae
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Yong-In Severance Hospital, Gyeongi-do, Korea. SW0615@yuhs.ac.
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Gyeongi-do, Korea. khj04@cha.ac.kr.
authors.forename: Hyung Jong
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. hask1951@yuhs.ac.
authors.forename: Sung Kyu
authors.initials: SK
authors.lastname: Ha
authors.affiliation: Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. amp97@yuhs.ac.|Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul, Korea. amp97@yuhs.ac.
authors.forename: Hyeong Cheon
authors.initials: HC
authors.lastname: Park
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D018920:Coculture Techniques; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005355:Fibrosis / Q000473:pathology / Q000628:therapy; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D007684:Kidney Tubules / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D009395:Nephritis, Interstitial / Q000628:therapy; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014517:Ureteral Obstruction / Q000473:pathology / Q000628:therapy*
chemical_list: D000199:Actins; D000943:Antigens, Differentiation; D016212:Transforming Growth Factor beta; C544013:alpha-smooth muscle actin, mouse; C036763:monocyte-macrophage differentiation antigen