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Exp Neurol. 2018 Oct;308:120-131. doi: 10.1016/j.expneurol.2018.07.006. Epub 2018 Jul 20.

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

Author information

1
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia.
2
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia.
3
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia. Electronic address: suzie.miller@monash.edu.

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

PMID:
30012511
DOI:
10.1016/j.expneurol.2018.07.006
[Indexed for MEDLINE]

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