Preterm umbilical cord blood derived mesenchymal stem/stromal cells protect preterm white matter brain development against hypoxia-ischemia

Jingang Li, Tamara Yawno, Amy E. Sutherland, Shanti Gurung, Madison Paton, Courtney McDonald, Abhilasha Tiwari, Yen Pham, Margie Castillo-Melendez, Graham Jenkin, Suzanne L. Miller

Research output: Contribution to journalArticleResearchpeer-review

5 Citations (Scopus)

Abstract

Introduction: Preterm infants are at high risk for white matter injury and subsequent neurodevelopmental impairments. Mesenchymal stem/stromal cells (MSC) have anti-inflammatory/immunomodulatory actions and are of interest for neural repair in adults and newborns. This study examined the neuroprotective effects of allogeneic MSC, derived from preterm umbilical cord blood (UCB), in a preterm sheep model of white matter injury. Methods: Quad-lineage differentiation, clonogenicity and self-renewal ability of UCB-derived MSC were confirmed. Chronically instrumented fetal sheep (0.7 gestation) received either 25 min hypoxia-ischemia (HI) to induce preterm brain injury, or sham-HI. Ten million MSC, or saline, were administered iv to fetuses at 12 h after HI. Fetal brains were collected 10d after HI for histopathology and immunocytochemistry. Results: HI induced white matter injury, as indicated by a reduction in CNPase-positive myelin fiber density. HI also induced microglial activation (Iba-1) in the periventricular white matter and internal capsule (P <.05 vs control). MSC administration following HI preserved myelination (P <.05), modified microglial activation, and promoted macrophage migration (CD163) and cell proliferation (Ki-67) within cerebral white matter (P <.05). Cerebral CXCL10 concentration was increased following MSC administration (P <.05), which was likely associated with macrophage migration and cell proliferation within the preterm brain. Additionally, MSC administration reduced systemic pro-inflammatory cytokine TNFα at 3d post-HI (P <.05). Conclusions: UCB-derived MSC therapy preserved white matter brain structure following preterm HI, mediated by a suppression of microglial activation, promotion of macrophage migration and acceleration of self-repair within the preterm brain. UCB-derived MSC are neuroprotective, acting via peripheral and cerebral anti-inflammatory and immunomodulatory mechanisms.

Original languageEnglish
Pages (from-to)120-131
Number of pages12
JournalExperimental Neurology
Volume308
DOIs
Publication statusPublished - 1 Oct 2018

Keywords

  • Cell transplantation
  • Cytokines
  • Mesenchymal stem cells
  • Oligodendrocytes
  • Stem cell expansion
  • Umbilical cord blood

Cite this

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title = "Preterm umbilical cord blood derived mesenchymal stem/stromal cells protect preterm white matter brain development against hypoxia-ischemia",
abstract = "Introduction: Preterm infants are at high risk for white matter injury and subsequent neurodevelopmental impairments. Mesenchymal stem/stromal cells (MSC) have anti-inflammatory/immunomodulatory actions and are of interest for neural repair in adults and newborns. This study examined the neuroprotective effects of allogeneic MSC, derived from preterm umbilical cord blood (UCB), in a preterm sheep model of white matter injury. Methods: Quad-lineage differentiation, clonogenicity and self-renewal ability of UCB-derived MSC were confirmed. Chronically instrumented fetal sheep (0.7 gestation) received either 25 min hypoxia-ischemia (HI) to induce preterm brain injury, or sham-HI. Ten million MSC, or saline, were administered iv to fetuses at 12 h after HI. Fetal brains were collected 10d after HI for histopathology and immunocytochemistry. Results: HI induced white matter injury, as indicated by a reduction in CNPase-positive myelin fiber density. HI also induced microglial activation (Iba-1) in the periventricular white matter and internal capsule (P <.05 vs control). MSC administration following HI preserved myelination (P <.05), modified microglial activation, and promoted macrophage migration (CD163) and cell proliferation (Ki-67) within cerebral white matter (P <.05). Cerebral CXCL10 concentration was increased following MSC administration (P <.05), which was likely associated with macrophage migration and cell proliferation within the preterm brain. Additionally, MSC administration reduced systemic pro-inflammatory cytokine TNFα at 3d post-HI (P <.05). Conclusions: UCB-derived MSC therapy preserved white matter brain structure following preterm HI, mediated by a suppression of microglial activation, promotion of macrophage migration and acceleration of self-repair within the preterm brain. UCB-derived MSC are neuroprotective, acting via peripheral and cerebral anti-inflammatory and immunomodulatory mechanisms.",
keywords = "Cell transplantation, Cytokines, Mesenchymal stem cells, Oligodendrocytes, Stem cell expansion, Umbilical cord blood",
author = "Jingang Li and Tamara Yawno and Sutherland, {Amy E.} and Shanti Gurung and Madison Paton and Courtney McDonald and Abhilasha Tiwari and Yen Pham and Margie Castillo-Melendez and Graham Jenkin and Miller, {Suzanne L.}",
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Preterm umbilical cord blood derived mesenchymal stem/stromal cells protect preterm white matter brain development against hypoxia-ischemia. / Li, Jingang; Yawno, Tamara; Sutherland, Amy E.; Gurung, Shanti; Paton, Madison; McDonald, Courtney; Tiwari, Abhilasha; Pham, Yen; Castillo-Melendez, Margie; Jenkin, Graham; Miller, Suzanne L.

In: Experimental Neurology, Vol. 308, 01.10.2018, p. 120-131.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Preterm umbilical cord blood derived mesenchymal stem/stromal cells protect preterm white matter brain development against hypoxia-ischemia

AU - Li, Jingang

AU - Yawno, Tamara

AU - Sutherland, Amy E.

AU - Gurung, Shanti

AU - Paton, Madison

AU - McDonald, Courtney

AU - Tiwari, Abhilasha

AU - Pham, Yen

AU - Castillo-Melendez, Margie

AU - Jenkin, Graham

AU - Miller, Suzanne L.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - Introduction: Preterm infants are at high risk for white matter injury and subsequent neurodevelopmental impairments. Mesenchymal stem/stromal cells (MSC) have anti-inflammatory/immunomodulatory actions and are of interest for neural repair in adults and newborns. This study examined the neuroprotective effects of allogeneic MSC, derived from preterm umbilical cord blood (UCB), in a preterm sheep model of white matter injury. Methods: Quad-lineage differentiation, clonogenicity and self-renewal ability of UCB-derived MSC were confirmed. Chronically instrumented fetal sheep (0.7 gestation) received either 25 min hypoxia-ischemia (HI) to induce preterm brain injury, or sham-HI. Ten million MSC, or saline, were administered iv to fetuses at 12 h after HI. Fetal brains were collected 10d after HI for histopathology and immunocytochemistry. Results: HI induced white matter injury, as indicated by a reduction in CNPase-positive myelin fiber density. HI also induced microglial activation (Iba-1) in the periventricular white matter and internal capsule (P <.05 vs control). MSC administration following HI preserved myelination (P <.05), modified microglial activation, and promoted macrophage migration (CD163) and cell proliferation (Ki-67) within cerebral white matter (P <.05). Cerebral CXCL10 concentration was increased following MSC administration (P <.05), which was likely associated with macrophage migration and cell proliferation within the preterm brain. Additionally, MSC administration reduced systemic pro-inflammatory cytokine TNFα at 3d post-HI (P <.05). Conclusions: UCB-derived MSC therapy preserved white matter brain structure following preterm HI, mediated by a suppression of microglial activation, promotion of macrophage migration and acceleration of self-repair within the preterm brain. UCB-derived MSC are neuroprotective, acting via peripheral and cerebral anti-inflammatory and immunomodulatory mechanisms.

AB - Introduction: Preterm infants are at high risk for white matter injury and subsequent neurodevelopmental impairments. Mesenchymal stem/stromal cells (MSC) have anti-inflammatory/immunomodulatory actions and are of interest for neural repair in adults and newborns. This study examined the neuroprotective effects of allogeneic MSC, derived from preterm umbilical cord blood (UCB), in a preterm sheep model of white matter injury. Methods: Quad-lineage differentiation, clonogenicity and self-renewal ability of UCB-derived MSC were confirmed. Chronically instrumented fetal sheep (0.7 gestation) received either 25 min hypoxia-ischemia (HI) to induce preterm brain injury, or sham-HI. Ten million MSC, or saline, were administered iv to fetuses at 12 h after HI. Fetal brains were collected 10d after HI for histopathology and immunocytochemistry. Results: HI induced white matter injury, as indicated by a reduction in CNPase-positive myelin fiber density. HI also induced microglial activation (Iba-1) in the periventricular white matter and internal capsule (P <.05 vs control). MSC administration following HI preserved myelination (P <.05), modified microglial activation, and promoted macrophage migration (CD163) and cell proliferation (Ki-67) within cerebral white matter (P <.05). Cerebral CXCL10 concentration was increased following MSC administration (P <.05), which was likely associated with macrophage migration and cell proliferation within the preterm brain. Additionally, MSC administration reduced systemic pro-inflammatory cytokine TNFα at 3d post-HI (P <.05). Conclusions: UCB-derived MSC therapy preserved white matter brain structure following preterm HI, mediated by a suppression of microglial activation, promotion of macrophage migration and acceleration of self-repair within the preterm brain. UCB-derived MSC are neuroprotective, acting via peripheral and cerebral anti-inflammatory and immunomodulatory mechanisms.

KW - Cell transplantation

KW - Cytokines

KW - Mesenchymal stem cells

KW - Oligodendrocytes

KW - Stem cell expansion

KW - Umbilical cord blood

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U2 - 10.1016/j.expneurol.2018.07.006

DO - 10.1016/j.expneurol.2018.07.006

M3 - Article

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EP - 131

JO - Experimental Neurology

JF - Experimental Neurology

SN - 0014-4886

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