Publication Date:
2014-01-07
Description:
There are no clinically relevant treatments available that improve function in the growing population of very preterm infants (less than 32 weeks' gestation) with neonatal brain injury. Diffuse white matter injury (DWMI) is a common finding in these children and results in chronic neurodevelopmental impairments. As shown recently, failure in oligodendrocyte progenitor cell maturation contributes to DWMI. We demonstrated previously that the epidermal growth factor receptor (EGFR) has an important role in oligodendrocyte development. Here we examine whether enhanced EGFR signalling stimulates the endogenous response of EGFR-expressing progenitor cells during a critical period after brain injury, and promotes cellular and behavioural recovery in the developing brain. Using an established mouse model of very preterm brain injury, we demonstrate that selective overexpression of human EGFR in oligodendrocyte lineage cells or the administration of intranasal heparin-binding EGF immediately after injury decreases oligodendroglia death, enhances generation of new oligodendrocytes from progenitor cells and promotes functional recovery. Furthermore, these interventions diminish ultrastructural abnormalities and alleviate behavioural deficits on white-matter-specific paradigms. Inhibition of EGFR signalling with a molecularly targeted agent used for cancer therapy demonstrates that EGFR activation is an important contributor to oligodendrocyte regeneration and functional recovery after DWMI. Thus, our study provides direct evidence that targeting EGFR in oligodendrocyte progenitor cells at a specific time after injury is clinically feasible and potentially applicable to the treatment of premature children with white matter injury.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4106485/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4106485/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Scafidi, Joseph -- Hammond, Timothy R -- Scafidi, Susanna -- Ritter, Jonathan -- Jablonska, Beata -- Roncal, Maria -- Szigeti-Buck, Klara -- Coman, Daniel -- Huang, Yuegao -- McCarter, Robert J Jr -- Hyder, Fahmeed -- Horvath, Tamas L -- Gallo, Vittorio -- DP1 OD006850/OD/NIH HHS/ -- K08 NS069815/NS/NINDS NIH HHS/ -- K08 NS073793/NS/NINDS NIH HHS/ -- K08NS069815/NS/NINDS NIH HHS/ -- K08NS073793/NS/NINDS NIH HHS/ -- K12NS052159/NS/NINDS NIH HHS/ -- P01 NS062686/NS/NINDS NIH HHS/ -- P30 HD040677/HD/NICHD NIH HHS/ -- P30 NS05219/NS/NINDS NIH HHS/ -- P30 NS052519/NS/NINDS NIH HHS/ -- P30HD040677/HD/NICHD NIH HHS/ -- R01 NS045702/NS/NINDS NIH HHS/ -- R01MH067528/MH/NIMH NIH HHS/ -- R01NS045702/NS/NINDS NIH HHS/ -- R01NS056427/NS/NINDS NIH HHS/ -- England -- Nature. 2014 Feb 13;506(7487):230-4. doi: 10.1038/nature12880. Epub 2013 Dec 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Neuroscience Research, Children's National Medical Center, Washington DC 20010, USA [2] Department of Neurology, Children's National Medical Center, Washington DC 20010, USA. ; 1] Center for Neuroscience Research, Children's National Medical Center, Washington DC 20010, USA [2] Institute for Biomedical Sciences, The George Washington University, Washington DC 20052, USA. ; Department of Anesthesiology & Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. ; Center for Neuroscience Research, Children's National Medical Center, Washington DC 20010, USA. ; Department of Neurobiology, Yale University, New Haven, Connecticut 06520, USA. ; MRRC, Department of Diagnostic Radiology, Yale University, New Haven, Connecticut 06520, USA. ; Center for Translational Science, Children's National Medical Center, Washington DC 20010, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24390343" target="_blank"〉PubMed〈/a〉
Keywords:
Administration, Intranasal
;
Animals
;
Animals, Newborn
;
Anoxia/genetics/metabolism/pathology/physiopathology
;
Brain Injuries/*congenital/*drug therapy/pathology/prevention & control
;
Cell Differentiation/drug effects
;
Cell Division/drug effects
;
Cell Lineage/drug effects
;
Cell Survival/drug effects
;
Demyelinating Diseases/congenital/metabolism/pathology/prevention & control
;
Disease Models, Animal
;
Epidermal Growth Factor/administration & dosage/*pharmacology/*therapeutic use
;
Humans
;
Infant, Premature, Diseases/drug therapy/metabolism/pathology
;
Male
;
Mice
;
Molecular Targeted Therapy
;
Oligodendroglia/cytology/*drug effects/metabolism/pathology
;
Receptor, Epidermal Growth Factor/genetics/metabolism
;
Regeneration/drug effects
;
Signal Transduction/drug effects
;
Stem Cells/cytology/drug effects/metabolism
;
Time Factors
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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