Human umbilical cord blood therapy protects cerebral white matter from systemic LPS exposure in preterm fetal sheep

Madison C.B. Paton, Beth J. Allison, Jingang Li, Michael C. Fahey, Amy E. Sutherland, Ilias Nitsos, Robert J. Bischof, Justin M. Dean, Timothy J.M. Moss, Graeme R. Polglase, Graham Jenkin, Courtney A. McDonald, Suzanne L. Miller

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: Infants born preterm following exposure to in utero inflammation/chorioamnionitis are at high risk of brain injury and life-long neurological deficits. In this study, we assessed the efficacy of early intervention umbilical cord blood (UCB) cell therapy in a large animal model of preterm brain inflammation and injury. We hypothesised that UCB treatment would be neuroprotective for the preterm brain following subclinical fetal inflammation. Methods: Chronically instrumented fetal sheep at 0.65 gestation were administered lipopolysaccharide (LPS, 150 ng, 055:B5) intravenously over 3 consecutive days, followed by 100 million human UCB mononuclear cells 6 h after the final LPS dose. Controls were administered saline instead of LPS and cells. Ten days after the first LPS dose, the fetal brain and cerebrospinal fluid were collected for analysis of subcortical and periventricular white matter injury and inflammation. Results: LPS administration increased microglial aggregate size, neutrophil recruitment, astrogliosis and cell death compared with controls. LPS also reduced total oligodendrocyte count and decreased mature myelinating oligodendrocytes. UCB cell therapy attenuated cell death and inflammation, and recovered total and mature oligodendrocytes, compared with LPS. Conclusions: UCB cell treatment following inflammation reduces preterm white matter brain injury, likely mediated via anti-inflammatory actions.

Original languageEnglish
Pages (from-to)258-270
Number of pages13
JournalDevelopmental Neuroscience
Volume40
Issue number3
DOIs
Publication statusPublished - 1 Oct 2018

Keywords

  • Brain injury
  • Cerebral palsy
  • Fetal sheep
  • Infection
  • Inflammation
  • Neonatal neuroinflammation
  • Stem cells
  • White matter
  • White matter damage

Cite this

@article{c8c7581f0a9b44eabf0f9a7a9a70cb4b,
title = "Human umbilical cord blood therapy protects cerebral white matter from systemic LPS exposure in preterm fetal sheep",
abstract = "Background: Infants born preterm following exposure to in utero inflammation/chorioamnionitis are at high risk of brain injury and life-long neurological deficits. In this study, we assessed the efficacy of early intervention umbilical cord blood (UCB) cell therapy in a large animal model of preterm brain inflammation and injury. We hypothesised that UCB treatment would be neuroprotective for the preterm brain following subclinical fetal inflammation. Methods: Chronically instrumented fetal sheep at 0.65 gestation were administered lipopolysaccharide (LPS, 150 ng, 055:B5) intravenously over 3 consecutive days, followed by 100 million human UCB mononuclear cells 6 h after the final LPS dose. Controls were administered saline instead of LPS and cells. Ten days after the first LPS dose, the fetal brain and cerebrospinal fluid were collected for analysis of subcortical and periventricular white matter injury and inflammation. Results: LPS administration increased microglial aggregate size, neutrophil recruitment, astrogliosis and cell death compared with controls. LPS also reduced total oligodendrocyte count and decreased mature myelinating oligodendrocytes. UCB cell therapy attenuated cell death and inflammation, and recovered total and mature oligodendrocytes, compared with LPS. Conclusions: UCB cell treatment following inflammation reduces preterm white matter brain injury, likely mediated via anti-inflammatory actions.",
keywords = "Brain injury, Cerebral palsy, Fetal sheep, Infection, Inflammation, Neonatal neuroinflammation, Stem cells, White matter, White matter damage",
author = "Paton, {Madison C.B.} and Allison, {Beth J.} and Jingang Li and Fahey, {Michael C.} and Sutherland, {Amy E.} and Ilias Nitsos and Bischof, {Robert J.} and Dean, {Justin M.} and Moss, {Timothy J.M.} and Polglase, {Graeme R.} and Graham Jenkin and McDonald, {Courtney A.} and Miller, {Suzanne L.}",
year = "2018",
month = "10",
day = "1",
doi = "10.1159/000490943",
language = "English",
volume = "40",
pages = "258--270",
journal = "Developmental Neuroscience",
issn = "0378-5866",
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Human umbilical cord blood therapy protects cerebral white matter from systemic LPS exposure in preterm fetal sheep. / Paton, Madison C.B.; Allison, Beth J.; Li, Jingang; Fahey, Michael C.; Sutherland, Amy E.; Nitsos, Ilias; Bischof, Robert J.; Dean, Justin M.; Moss, Timothy J.M.; Polglase, Graeme R.; Jenkin, Graham; McDonald, Courtney A.; Miller, Suzanne L.

In: Developmental Neuroscience, Vol. 40, No. 3, 01.10.2018, p. 258-270.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Human umbilical cord blood therapy protects cerebral white matter from systemic LPS exposure in preterm fetal sheep

AU - Paton, Madison C.B.

AU - Allison, Beth J.

AU - Li, Jingang

AU - Fahey, Michael C.

AU - Sutherland, Amy E.

AU - Nitsos, Ilias

AU - Bischof, Robert J.

AU - Dean, Justin M.

AU - Moss, Timothy J.M.

AU - Polglase, Graeme R.

AU - Jenkin, Graham

AU - McDonald, Courtney A.

AU - Miller, Suzanne L.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - Background: Infants born preterm following exposure to in utero inflammation/chorioamnionitis are at high risk of brain injury and life-long neurological deficits. In this study, we assessed the efficacy of early intervention umbilical cord blood (UCB) cell therapy in a large animal model of preterm brain inflammation and injury. We hypothesised that UCB treatment would be neuroprotective for the preterm brain following subclinical fetal inflammation. Methods: Chronically instrumented fetal sheep at 0.65 gestation were administered lipopolysaccharide (LPS, 150 ng, 055:B5) intravenously over 3 consecutive days, followed by 100 million human UCB mononuclear cells 6 h after the final LPS dose. Controls were administered saline instead of LPS and cells. Ten days after the first LPS dose, the fetal brain and cerebrospinal fluid were collected for analysis of subcortical and periventricular white matter injury and inflammation. Results: LPS administration increased microglial aggregate size, neutrophil recruitment, astrogliosis and cell death compared with controls. LPS also reduced total oligodendrocyte count and decreased mature myelinating oligodendrocytes. UCB cell therapy attenuated cell death and inflammation, and recovered total and mature oligodendrocytes, compared with LPS. Conclusions: UCB cell treatment following inflammation reduces preterm white matter brain injury, likely mediated via anti-inflammatory actions.

AB - Background: Infants born preterm following exposure to in utero inflammation/chorioamnionitis are at high risk of brain injury and life-long neurological deficits. In this study, we assessed the efficacy of early intervention umbilical cord blood (UCB) cell therapy in a large animal model of preterm brain inflammation and injury. We hypothesised that UCB treatment would be neuroprotective for the preterm brain following subclinical fetal inflammation. Methods: Chronically instrumented fetal sheep at 0.65 gestation were administered lipopolysaccharide (LPS, 150 ng, 055:B5) intravenously over 3 consecutive days, followed by 100 million human UCB mononuclear cells 6 h after the final LPS dose. Controls were administered saline instead of LPS and cells. Ten days after the first LPS dose, the fetal brain and cerebrospinal fluid were collected for analysis of subcortical and periventricular white matter injury and inflammation. Results: LPS administration increased microglial aggregate size, neutrophil recruitment, astrogliosis and cell death compared with controls. LPS also reduced total oligodendrocyte count and decreased mature myelinating oligodendrocytes. UCB cell therapy attenuated cell death and inflammation, and recovered total and mature oligodendrocytes, compared with LPS. Conclusions: UCB cell treatment following inflammation reduces preterm white matter brain injury, likely mediated via anti-inflammatory actions.

KW - Brain injury

KW - Cerebral palsy

KW - Fetal sheep

KW - Infection

KW - Inflammation

KW - Neonatal neuroinflammation

KW - Stem cells

KW - White matter

KW - White matter damage

UR - http://www.scopus.com/inward/record.url?scp=85053025386&partnerID=8YFLogxK

U2 - 10.1159/000490943

DO - 10.1159/000490943

M3 - Article

VL - 40

SP - 258

EP - 270

JO - Developmental Neuroscience

JF - Developmental Neuroscience

SN - 0378-5866

IS - 3

ER -