title: Early, but not late, treatment with human umbilical cord blood-derived mesenchymal stem cells attenuates cisplatin nephrotoxicity through immunomodulation.
abstract: Preemptive treatment with mesenchymal stem cells (MSCs) can attenuate cisplatin-induced acute kidney injury (AKI). However, it is uncertain whether MSC treatment after the development of renal dysfunction prevents AKI progression or if MSC immunomodulatory properties contribute to MSC therapy. In this study, human umbilical cord blood (hUCB)-derived MSCs were used to compare the effects and mechanisms of early and late MSC therapy in a murine model. After cisplatin injection into C57BL/6 mice, hUCB-MSCs were administered onday 1(early treatment) orday 3(late treatment). With early treatment, cisplatin nephrotoxicity was attenuated as evidenced by decreased blood urea nitrogen (BUN) and reduced apoptosis and tubular injury scores onday 3Early treatment resulted in downregulation of intrarenal monocyte chemotactic protein-1 and IL-6 expression and upregulation of IL-10 and VEGF expression. Flow cytometric analysis showed similar populations of infiltrated immune cells in both groups; however, regulatory T-cell (Treg) infiltration was 2.5-fold higher in the early treatment group. The role of Tregs was confirmed by the blunted effect of early treatment on renal injury after Treg depletion. In contrast, late treatment (at a time when BUN levels were 2-fold higher than baseline levels) showed no renoprotective effects onday 6Neither the populations of intrarenal infiltrating immune cells (including Tregs) nor cytokine expression levels were affected by late treatment. Our results suggest that early MSC treatment attenuates renal injury by Treg induction and immunomodulation, whereas a late treatment (i.e., after the development of renal dysfunction) does not prevent AKI progression or alter the intrarenal inflammatory micromilieu.
authors.affiliation: Division of Nephrology, Department of Medicine, Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.|Department of Medicine, National Police Hospital, Seoul, Korea; and.
authors.forename: Ji Hyeon
authors.initials: JH
authors.lastname: Park
authors.affiliation: Division of Nephrology, Department of Medicine, Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Hye Ryoun
authors.initials: HR
authors.lastname: Jang
authors.affiliation: Division of Nephrology, Department of Medicine, Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.|Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Korea.
authors.forename: Do Hee
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Ghee Young
authors.initials: GY
authors.lastname: Kwon
authors.affiliation: Division of Nephrology, Department of Medicine, Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Lee
authors.affiliation: Division of Nephrology, Department of Medicine, Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Wooseong
authors.initials: W
authors.lastname: Huh
authors.affiliation: Biomedical Research Institute, R&D Center, Medipost Company, Gyeonggi-do, Korea.
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Choi
authors.affiliation: Biomedical Research Institute, R&D Center, Medipost Company, Gyeonggi-do, Korea.
authors.forename: Wonil
authors.initials: W
authors.lastname: Oh
authors.affiliation: Division of Nephrology, Department of Medicine, Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Ha Young
authors.initials: HY
authors.lastname: Oh
authors.affiliation: Division of Nephrology, Department of Medicine, Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; ygkim26@skku.edu.
authors.forename: Yoon-Goo
authors.initials: YG
authors.lastname: Kim
mesh_terms: D058186:Acute Kidney Injury / Q000276:immunology / Q000517:prevention & control*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002945:Cisplatin / Q000009:adverse effects*; D056747:Immunomodulation; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin
keywords: acute kidney injury; cisplatin nephrotoxicity; human umbilical cord-derived mesenchymal stem cells; immunomodulation; regulatory T cells