title: Epidermal growth factor preserves myelin and promotes astrogliosis after intraventricular hemorrhage.
abstract: Intraventricular hemorrhage (IVH) leads to reduced myelination and astrogliosis of the white matter in premature infants. No therapeutic strategy exists to minimize white matter injury in survivors with IVH. Epidermal growth factor (EGF) enhances myelination, astrogliosis, and neurologic recovery in animal models of white matter injury. Here, we hypothesized that recombinant human (rh) EGF treatment would enhance oligodendrocyte precursor cell (OPC) maturation, myelination, and neurological recovery in preterm rabbits with IVH. In addition, rhEGF would promote astrogliosis by inducing astroglial progenitor proliferation and GFAP transcription. We tested these hypotheses in a preterm rabbit model of IVH and evaluated autopsy samples from human preterm infants. We found that EGF and EGFR expression were more abundant in the ganglionic eminence relative to the cortical plate and white matter of human infants and that the development of IVH reduced EGF levels, but not EGFR expression. Accordingly, rhEGF treatment promoted proliferation and maturation of OPCs, preserved myelin in the white matter, and enhanced neurological recovery in rabbits with IVH. rhEGF treatment inhibited Notch signaling, which conceivably contributed to OPC maturation. rhEGF treatment contributed to astrogliosis by increasing astroglial proliferation and upregulating GFAP as well as Sox9 expression. Hence, IVH results in a decline in EGF expression; and rhEGF treatment preserves myelin, restores neurological recovery, and exacerbates astrogliosis by inducing proliferation of astrocytes and enhancing transcription of GFAP and Sox9 in pups with IVH. rhEGF treatment might improve the neurological outcome of premature infants with IVH. GLIA 2016;64:1987-2004.
authors.affiliation: Department of Pediatrics, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, New York.
authors.forename: Govindaiah
authors.initials: G
authors.lastname: Vinukonda
authors.affiliation: Department of Pediatrics, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, New York.
authors.forename: Furong
authors.initials: F
authors.lastname: Hu
authors.affiliation: Department of Cell Biology and Anatomy, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, New York.
authors.forename: Rana
authors.initials: R
authors.lastname: Mehdizadeh
authors.affiliation: Department of Pediatrics, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, New York.
authors.forename: Preeti
authors.initials: P
authors.lastname: Dohare
authors.affiliation: Department of Pediatrics, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, New York.
authors.forename: Ali
authors.initials: A
authors.lastname: Kidwai
authors.affiliation: Department of Pediatrics, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, New York.
authors.forename: Ankit
authors.initials: A
authors.lastname: Juneja
authors.affiliation: Department of Pediatrics, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, New York.
authors.forename: Vineet
authors.initials: V
authors.lastname: Naran
authors.affiliation: Department of Pediatrics, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, New York.
authors.forename: Maria
authors.initials: M
authors.lastname: Kierstead
authors.affiliation: Department of Pediatrics, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, New York.
authors.forename: Rachit
authors.initials: R
authors.lastname: Chawla
authors.affiliation: Department of Anatomical Pathology, Oregon Health and Science University, Portland, Oregon.
authors.forename: Robert
authors.initials: R
authors.lastname: Kayton
authors.affiliation: Department of Pediatrics, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, New York. pballabh@msn.com.|Department of Cell Biology and Anatomy, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, New York. pballabh@msn.com.
authors.forename: Praveen
authors.initials: P
authors.lastname: Ballabh
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000648:ultrastructure; D001921:Brain / Q000196:embryology / Q000254:growth & development / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D000074042:Cerebral Intraventricular Hemorrhage / Q000139:chemically induced / Q000150:complications* / Q000473:pathology*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000209:etiology*; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D019394:Ki-67 Antigen / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism*; D000076104:Oligodendrocyte Transcription Factor 2 / Q000378:metabolism; D009836:Oligodendroglia / Q000473:pathology / Q000648:ultrastructure; D011817:Rabbits; D015398:Signal Transduction / Q000502:physiology
chemical_list: D005904:Glial Fibrillary Acidic Protein; D019394:Ki-67 Antigen; D000076104:Oligodendrocyte Transcription Factor 2; D004815:Epidermal Growth Factor
keywords: astrogliosis; epidermal growth factor; intraventricular hemorrhage; myelination; oligodendrocyte progenitor cells; premature infants