title: Ischemic brain injury: a consortium analysis of key factors involved in mesenchymal stem cell-mediated inflammatory reduction.
abstract: Increasing global birth rate, coupled with the aging population surviving into their eighth decade has lead to increased incidence diseases, hitherto designated as rare. Brain related ischemia, at birth, or later in life, during, for example stroke, is increasing in global prevalence. Reactive microglia can contribute to neuronal damage as well as compromising transplantion. One potential treatment strategy is cellular therapy, using mesenchymal stem cells (hMSCs), which possess immunomodulatory and cell repair properties. For effective clinical therapy, mechanisms of action must be understood better. Here multicentre international laboratories assessed this question together investigating application of hMSCs neural involvement, with interest in the role of reactive microglia. Modulation by hMSCs in our in vivo and in vitro study shows they decrease markers of microglial activation (lower ED1 and Iba) and astrogliosis (lower GFAP) following transplantation in an ouabain-induced brain ischemia rat model and in organotypic hippocampal cultures. The anti-inflammatory effect in vitro was demonstrated to be CD200 ligand dependent with ligand expression shown to be increased by IL-4 stimulation. hMSC transplant reduced rat microglial STAT3 gene expression and reduced activation of Y705 phosphorylated STAT3, but STAT3 in the hMSCs themselves was elevated upon grafting. Surprisingly, activity was dependent on heterodimerisation with STAT1 activated by IL-4 and Oncostatin M. Our study paves the way to preclinical stages of a clinical trial with hMSC, and suggests a non-canonical JAK-STAT signaling of unphosphorylated STAT3 in immunomodulatory effects of hMSCs.
authors: Cell Therapy Research Institute CTI-LYON, B1, 5 Avenue Lionel Terray, 69330 Meyzieu-LYON, France. c.mcguckin@conoworld.com
authors: Colin P
authors: CP
authors: McGuckin
authors: Marcin
authors: M
authors: Jurga
authors: Anne-Marie
authors: AM
authors: Miller
authors: Anna
authors: A
authors: Sarnowska
authors: Marc
authors: M
authors: Wiedner
authors: Noreen T
authors: NT
authors: Boyle
authors: Marina A
authors: MA
authors: Lynch
authors: Anna
authors: A
authors: Jablonska
authors: Katarzyna
authors: K
authors: Drela
authors: Barbara
authors: B
authors: Lukomska
authors: Krystyna
authors: K
authors: Domanska-Janik
authors: Lukas
authors: L
authors: Kenner
authors: Richard
authors: R
authors: Moriggl
authors: Olivier
authors: O
authors: Degoul
authors: Claire
authors: C
authors: Perruisseau-Carrier
authors: Nico
authors: N
authors: Forraz
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D015153:Blotting, Western; D001930:Brain Injuries / Q000276:immunology* / Q000378:metabolism; D002545:Brain Ischemia / Q000276:immunology / Q000378:metabolism*; D019013:CD40 Antigens / Q000235:genetics; D018920:Coculture Techniques; D053331:Ectodysplasins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007155:Immunologic Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D017628:Microglia / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D023421:Models, Animal; D010766:Phosphorylation; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014470:Umbilical Cord / Q000166:cytology
chemical_list: D015703:Antigens, CD; D019013:CD40 Antigens; C506018:EDA protein, human; D053331:Ectodysplasins; D007155:Immunologic Factors; D053583:Interleukin-1beta; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015847:Interleukin-4; C042739:antigens, CD200