title: Human marrow-derived mesenchymal stromal cells decrease cisplatin renotoxicity in vitro and in vivo and enhance survival of mice post-intraperitoneal injection.
abstract: Acute kidney injury (AKI) can occur from the toxic side-effects of chemotherapeutic agents such as cisplatin. Bone marrow-derived mesenchymal stromal cells (MSCs) have demonstrated wide therapeutic potential often due to beneficial factors they secrete. The goal of this investigation was to evaluate in vitro the effect of human MSCs (hMSCs) secretome on cisplatin-treated human kidney cells, and in vivo the consequence of hMSCs intraperitoneal (ip) implantation in mice with AKI. Our results revealed that hMSCs-conditioned media improved survival of HK-2 human proximal tubular cells exposed to cisplatin in vitro. This enhanced survival was linked to increased expression of phosphorylated Akt (Ser473) and was reduced by a VEGF-neutralizing antibody. In vivo testing of these hMSCs established that ip administration in NOD-SCID mice decreased cisplatin-induced kidney function impairment, as demonstrated by lower blood urea nitrogen levels and higher survival. In addition, blood phosphorous and amylase levels were also significantly decreased. Moreover, hMSCs reduced the plasma levels of several inflammatory cytokines/chemokines. Immunohistochemical examination of kidneys showed less apoptotic and more proliferating cells. Furthermore, PCR indicated the presence of hMSCs in mouse kidneys, which also showed enhanced expression of phosphorylated Akt. In conclusion, our study reveals that hMSCs can exert prosurvival effects on renal cells in vitro and in vivo, suggests a paracrine contribution for kidney protective abilities of hMSCs delivered ip, and supports their clinical potential in AKI.
authors.affiliation: Lady Davis Institute for Medical Research and Dept. of Surgery, McGill Univ., 3755 Cote Ste.-Catherine Rd., Montreal, Quebec, Canada H3T-1E2. neliopou@ldi.jgh.mcgill.ca
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Eliopoulos
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Manaf
authors.initials: M
authors.lastname: Bouchentouf
authors.forename: Kathy
authors.initials: K
authors.lastname: Forner
authors.forename: Elena
authors.initials: E
authors.lastname: Birman
authors.forename: Shala
authors.initials: S
authors.lastname: Yuan
authors.forename: Marie-Noelle
authors.initials: MN
authors.lastname: Boivin
authors.forename: Daniel
authors.initials: D
authors.lastname: Martineau
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000009:adverse effects*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000097:blood; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017154:Stromal Cells / Q000502:physiology
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin