Preterm white matter brain injury is prevented by early administration of umbilical cord blood cells.
Infants born very preterm are at high risk for neurological deficits including cerebral palsy. In this study we assessed the neuroprotective effects of umbilical cord blood cells (UCBCs) and optimal administration timing in a fetal sheep model of preterm brain injury. 50 million allogeneic UCBCs were intravenously administered to fetal sheep (0.7 gestation) at 12h or 5d after acute hypoxia-ischemia (HI) induced by umbilical cord occlusion. The fetal brains were collected at 10d after HI. HI (n=7) was associated with reduced number of oligodendrocytes (Olig2+) and myelin density (CNPase+), and increased density of activated microglia (Iba-1+) in cerebral white matter compared to control fetuses (P<0.05). UCBCs administered at 12h, but not 5d after HI, significantly protected white matter structures and suppressed cerebral inflammation. Activated microglial density showed a correlation with decreasing oligodendrocyte number (P<0.001). HI caused cell death (TUNEL+) in the internal capsule and cell proliferation (Ki-67+) in the subventricular zone compared to control (P<0.05), while UCBCs at 12h or 5d ameliorated these effects. Additionally, UCBCs at 12h induced a significant systemic increase in interleukin-10 at 10d, and reduced oxidative stress (malondialdehyde) following HI (P<0.05). UCBC administration at 12h after HI reduces preterm white matter injury, via anti-inflammatory and antioxidant actions.
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia.
Jingang
J
Li
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia.
Tamara
T
Yawno
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia.
Amy
A
Sutherland
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia.
Jan
J
Loose
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia.
Ilias
I
Nitsos
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia.
Robert
R
Bischof
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia.
Margie
M
Castillo-Melendez
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia.
Courtney A
CA
McDonald
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Paediatrics, Monash Medical Centre, Clayton, VIC, Australia.
Flora Y
FY
Wong
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia.
Graham
G
Jenkin
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia.
Suzanne L
SL
Miller
D000818:Animals; D000831:Animals, Newborn; D001919:Bradycardia / Q000209:etiology; D001930:Brain Injuries / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control*; D036101:Cord Blood Stem Cell Transplantation / Q000379:methods*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005260:Female; D005865:Gestational Age; D007022:Hypotension / Q000209:etiology; D020925:Hypoxia-Ischemia, Brain / Q000150:complications; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009836:Oligodendroglia / Q000473:pathology; D011247:Pregnancy; D012756:Sheep; D013997:Time Factors; D066127:White Matter / Q000473:pathology*
D016207:Cytokines; D019394:Ki-67 Antigen; D009419:Nerve Tissue Proteins; D008315:Malondialdehyde
Hypoxia-ischemia; Neuroprotection; Oligodendrocytes; Preterm infants; Stem cell; Umbilical cord blood therapy; White matter brain injury