Transplanted glial restricted precursor cells improve neurobehavioral and neuropathological outcomes in a mouse model of neonatal white matter injury despite limited cell survival.
OBJECTIVE
Neonatal white matter injury (NWMI) is the leading cause of cerebral palsy and other neurocognitive deficits in prematurely-born children, and no restorative therapies exist. Our objective was to determine the fate and effect of glial restricted precursor cell (GRP) transplantation in an ischemic mouse model of NWMI.


METHODS
Neonatal CD-1 mice underwent unilateral carotid artery ligation on postnatal-Day 5 (P5). At P22, intracallosal injections of either enhanced green fluorescent protein (eGFP) + GRPs or saline were performed in control and ligated mice. Neurobehavioral and postmortem studies were performed at 4 and 8 weeks post-transplantation.


RESULTS
GRP survival was comparable at 1 month but significantly lower at 2 months post-transplantation in NWMI mice compared with unligated controls. Surviving cells showed better migration capability in controls; however, the differentiation capacity of transplanted cells was similar in control and NWMI. Saline-treated NWMI mice showed significantly altered response in startle amplitude and prepulse inhibition (PPI) paradigms compared with unligated controls, while these behavioral tests were completely normal in GRP-transplanted animals. Similarly, there was significant increase in hemispheric myelin basic protein density, along with significant decrease in pathologic axonal staining in cell-treated NWMI mice compared with saline-treated NWMI animals.


CONCLUSIONS
The reduced long-term survival and migration of transplanted GRPs in an ischemia-induced NWMI model suggests that neonatal ischemia leads to long-lasting detrimental effects on oligodendroglia even months after the initial insult. Despite limited GRP-survival, behavioral, and neuropathological outcomes were improved after GRP-transplantation. Our results suggest that exogenous GRPs improve myelination through trophic effects in addition to differentiation into mature oligodendrocytes.
Kennedy Krieger Institute, Johns Hopkins University, Baltimore, Maryland.
Michael
M
Porambo
Andre W
AW
Phillips
Joel
J
Marx
Kylie
K
Ternes
Edwin
E
Arauz
Mikhail
M
Pletnikov
Mary Ann
MA
Wilson
Jeffery D
JD
Rothstein
Michael V
MV
Johnston
Ali
A
Fatemi
D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000473:pathology / Q000502:physiology; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology*; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002470:Cell Survival / Q000502:physiology*; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000378:metabolism; D009457:Neuroglia / Q000502:physiology / Q000637:transplantation*; D013116:Spinal Cord / Q000502:physiology / Q000637:transplantation; D033581:Stem Cell Transplantation / Q000379:methods; D013234:Stem Cells / Q000502:physiology*; D016896:Treatment Outcome; D066127:White Matter / Q000293:injuries* / Q000473:pathology / Q000503:physiopathology
D004676:Myelin Basic Protein; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins
cell therapy; cerebral palsy; ischemia; myelination