Ischemic brain injury: A consortium analysis of key factors involved in mesenchymal stem cell-mediated inflammatory reduction

Colin P. McGuckin, Marcin Jurga, Anne Marie Miller, Anna Sarnowska, Marc Wiedner, Noreen T. Boyle, Marina A. Lynch, Anna Jablonska, Katarzyna Drela, Barbara Lukomska, Krystyna Domanska-Janik, Lukas Kenner, Richard Moriggl, Olivier Degoul, Claire Perruisseau-Carrier, Nico Forraz

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)88-97
Number of pages10
JournalArchives of Biochemistry and Biophysics
Volume534
Issue number1-2
DOIs
StatePublished - Jun 1 2013
Externally publishedYes

Fingerprint

Microglia
Stem cells
Brain Ischemia
Mesenchymal Stromal Cells
Interleukin-4
Brain Injuries
Statistical Factor Analysis
Rats
Brain
Chemical activation
Oncostatin M
Ligands
Transplants
Birth Rate
Ouabain
Gene expression
Repair
Anti-Inflammatory Agents
Aging of materials
Transplantation

Keywords

  • Inflammation
  • Ischemia
  • JAK-STAT signaling
  • Mesenchymal stem cells
  • Stroke

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

Cite this

Ischemic brain injury : A consortium analysis of key factors involved in mesenchymal stem cell-mediated inflammatory reduction. / McGuckin, Colin P.; Jurga, Marcin; Miller, Anne Marie; Sarnowska, Anna; Wiedner, Marc; Boyle, Noreen T.; Lynch, Marina A.; Jablonska, Anna; Drela, Katarzyna; Lukomska, Barbara; Domanska-Janik, Krystyna; Kenner, Lukas; Moriggl, Richard; Degoul, Olivier; Perruisseau-Carrier, Claire; Forraz, Nico.

In: Archives of Biochemistry and Biophysics, Vol. 534, No. 1-2, 01.06.2013, p. 88-97.

Research output: Contribution to journalArticle

McGuckin, CP, Jurga, M, Miller, AM, Sarnowska, A, Wiedner, M, Boyle, NT, Lynch, MA, Jablonska, A, Drela, K, Lukomska, B, Domanska-Janik, K, Kenner, L, Moriggl, R, Degoul, O, Perruisseau-Carrier, C & Forraz, N 2013, 'Ischemic brain injury: A consortium analysis of key factors involved in mesenchymal stem cell-mediated inflammatory reduction', Archives of Biochemistry and Biophysics, vol. 534, no. 1-2, pp. 88-97. https://doi.org/10.1016/j.abb.2013.02.005
McGuckin, Colin P. ; Jurga, Marcin ; Miller, Anne Marie ; Sarnowska, Anna ; Wiedner, Marc ; Boyle, Noreen T. ; Lynch, Marina A. ; Jablonska, Anna ; Drela, Katarzyna ; Lukomska, Barbara ; Domanska-Janik, Krystyna ; Kenner, Lukas ; Moriggl, Richard ; Degoul, Olivier ; Perruisseau-Carrier, Claire ; Forraz, Nico. / Ischemic brain injury : A consortium analysis of key factors involved in mesenchymal stem cell-mediated inflammatory reduction. In: Archives of Biochemistry and Biophysics. 2013 ; Vol. 534, No. 1-2. pp. 88-97.
@article{a2542cd893224275af52e2bb0b891c79,
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.",
keywords = "Inflammation, Ischemia, JAK-STAT signaling, Mesenchymal stem cells, Stroke",
author = "McGuckin, {Colin P.} and Marcin Jurga and Miller, {Anne Marie} and Anna Sarnowska and Marc Wiedner and Boyle, {Noreen T.} and Lynch, {Marina A.} and Anna Jablonska and Katarzyna Drela and Barbara Lukomska and Krystyna Domanska-Janik and Lukas Kenner and Richard Moriggl and Olivier Degoul and Claire Perruisseau-Carrier and Nico Forraz",
year = "2013",
month = "6",
day = "1",
doi = "10.1016/j.abb.2013.02.005",
language = "English (US)",
volume = "534",
pages = "88--97",
journal = "Archives of Biochemistry and Biophysics",
issn = "0003-9861",
publisher = "Academic Press Inc.",
number = "1-2",

}

TY - JOUR

T1 - Ischemic brain injury

T2 - A consortium analysis of key factors involved in mesenchymal stem cell-mediated inflammatory reduction

AU - McGuckin, Colin P.

AU - Jurga, Marcin

AU - Miller, Anne Marie

AU - Sarnowska, Anna

AU - Wiedner, Marc

AU - Boyle, Noreen T.

AU - Lynch, Marina A.

AU - Jablonska, Anna

AU - Drela, Katarzyna

AU - Lukomska, Barbara

AU - Domanska-Janik, Krystyna

AU - Kenner, Lukas

AU - Moriggl, Richard

AU - Degoul, Olivier

AU - Perruisseau-Carrier, Claire

AU - Forraz, Nico

PY - 2013/6/1

Y1 - 2013/6/1

N2 - 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.

AB - 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.

KW - Inflammation

KW - Ischemia

KW - JAK-STAT signaling

KW - Mesenchymal stem cells

KW - Stroke

UR - http://www.scopus.com/inward/record.url?scp=84876818519&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876818519&partnerID=8YFLogxK

U2 - 10.1016/j.abb.2013.02.005

DO - 10.1016/j.abb.2013.02.005

M3 - Article

C2 - 23466243

AN - SCOPUS:84876818519

VL - 534

SP - 88

EP - 97

JO - Archives of Biochemistry and Biophysics

JF - Archives of Biochemistry and Biophysics

SN - 0003-9861

IS - 1-2

ER -