title: Impaired oligodendrocyte maturation in preterm infants: Potential therapeutic targets.
abstract: Preterm birth is an evolving challenge in neonatal health care. Despite declining mortality rates among extremely premature neonates, morbidity rates remain very high. Currently, perinatal diffuse white matter injury (WMI) is the most commonly observed type of brain injury in preterm infants and has become an important research area. Diffuse WMI is associated with impaired cognitive, sensory and psychological functioning and is increasingly being recognized as a risk factor for autism-spectrum disorders, ADHD, and other psychological disturbances. No treatment options are currently available for diffuse WMI and the underlying pathophysiological mechanisms are far from being completely understood. Preterm birth is associated with maternal inflammation, perinatal infections and disrupted oxygen supply which can affect the cerebral microenvironment by causing activation of microglia, astrogliosis, excitotoxicity, and oxidative stress. This intricate interplay of events negatively influences oligodendrocyte development, causing arrested oligodendrocyte maturation or oligodendrocyte cell death, which ultimately results in myelination failure in the developing white matter. This review discusses the current state in perinatal WMI research, ranging from a clinical perspective to basic molecular pathophysiology. The complex regulation of oligodendrocyte development in healthy and pathological conditions is described, with a specific focus on signaling cascades that may play a role in WMI. Furthermore, emerging concepts in the field of WMI and issues regarding currently available animal models are put forward. Novel insights into the molecular mechanisms underlying impeded oligodendrocyte maturation in diffuse WMI may aid the development of novel treatment options which are desperately needed to improve the quality-of-life of preterm neonates.
authors.affiliation: Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: van Tilborg
authors.affiliation: Laboratory of Neuroimmunology, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Cobi J
authors.initials: CJ
authors.lastname: Heijnen
authors.affiliation: Department of Neonatology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Manon J
authors.initials: MJ
authors.lastname: Benders
authors.affiliation: Department of Neonatology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: van Bel
authors.affiliation: Inserm, Paris U1141, France; Université Paris Diderot, Sorbonne Paris Cité, UMRS, Paris 1141, France; Centre for the Developing Brain, Department of Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, United Kingdom.
authors.forename: Bobbi
authors.initials: B
authors.lastname: Fleiss
authors.affiliation: Inserm, Paris U1141, France; Université Paris Diderot, Sorbonne Paris Cité, UMRS, Paris 1141, France; Centre for the Developing Brain, Department of Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, United Kingdom.
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
authors.affiliation: Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: C.Nijboer@umcutrecht.nl.
authors.forename: Cora H
authors.initials: CH
authors.lastname: Nijboer
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D007234:Infant, Premature / Q000502:physiology*; D056784:Leukoencephalopathies / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D009836:Oligodendroglia / Q000187:drug effects / Q000473:pathology / Q000502:physiology*
keywords: Astrogliosis; Microglia; Oligodendrocyte; Preterm birth; Therapeutic strategies; White matter injury