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Trophic factors are essential for the survival of grafted oligodendrocyte progenitors and for neuroprotection after perinatal excitotoxicity

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Neural Regeneration Research 2020年第3期15卷 557-568页

作者： Megumi Hirose-Ikeda Brian Chu Paul Zhao Omar Akil elida escalante Laurent Vergnes Carlos Cepeda Araceli Espinosa-Jeffrey Intellectual and Developmental Disabilities Research Center Jane and Terry Semel Institute for Neuroscience and Human BehaviorDepartments of NeurobiologyPsychiatry&Biobehavioral SciencesUniversity of CaliforniaLos AngelesCAUSA Department of Human Genetics David Geffen School of MedicineUniversity of CaliforniaLos AngelesCAUSA

The consequences of neonatal white matter injury are devastating and represent a major societal problem as currently there is no cure.Prematurity,low weight birth and maternal pre-natal infection are the most frequent causes of acquired myelin deficiency in the human neonate leading to cerebral palsy and cognitive impairment.In the developing brain,oligodendrocyte(OL)maturation occurs perinatally,and immature OLs are particularly vulnerable.Cell replacement therapy is often considered a viable option to replace progenitors that die due to glutamate excitotoxicity.We previously reported directed specification and mobilization of endogenous committed and uncommitted neural progenitors by the combination of transferrin and insulin growth factor 1(TSC1).Here,considering cell replacement and integration as therapeutic goals,we examined if OL progenitors(OLPs)grafted into the brain parenchyma of mice that were subjected to an excitotoxic insult could rescue white matter injury.For that purpose,we used a well-established model of glutamate excitotoxic injury.Four-day-old mice received a single intraparenchymal injection of the glutamate receptor agonist N-methyl-D-aspartate alone or in conjunction with TSC1 in the presence or absence of OLPs grafted into the brain parenchyma.Energetics and expression of stress proteins and OL developmental specific markers were examined.A comparison of the proteomic profile per treatment was also ascertained.We found that OLPs did not survive in the excitotoxic environment when grafted alone.In contrast,when combined with TSC1,survival and integration of grafted OLPs was observed.Further,energy metabolism in OLPs was significantly increased by N-methyl-D-aspartate and modulated by TSC1.The proteomic profile after the various treatments showed elevated ubiquitination and stress/heat shock protein 90 in response to N-methyl-D-aspartate.These changes were reversed in the presence of TSC1 and ubiquitination was decreased.The results obtained in this pre-clinical study indicate that the use

关键词： myelin regeneration myelination oligodendrocytes periventricular leukomalacia premature birth proteomics trophic factors white matter injury

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