Human periventricular white matter injury (PWMI) is the major form of brain injury and the leading cause of cerebral palsy in survivors of premature birth. With advances in neonatal care, diffuse myelination disturbances and cerebral gray matter atrophy are emerging as the major lesions associated with PWMI. We developed in preterm fetal sheep an in utero model of cerebral ischemia that preserves the maternal- fetal unit and generates a spectrum of acute and chronic cerebral injury that closely resembles that seen in preterm survivors. The predilection for acute white matter injury was defined by the regional distribution of late oligdendrocyte (OL) progenitors (preOLs) that were found to be selectively vulnerable to ischemia. We, thus, hypothesized that the acute degeneration of preOLs depletes the white matter of mature OLs required for myelination. However, as white matter injury evolves, myelination failure coincides with diffuse astrogliosis and an expanding population of preOLs that re-populate the lesions but fail to differentiate and myelinate despite the presence of numerous intact axons. These unexpected findings suggest the alternative overall hypothesis that myelination failure is related to diffuse gliosis and an arrest of OL maturation at pre-myelinating stages. We further hypothesize that arrest of preOL maturation at this OL stage, that is highly susceptible to ischemia, predisposes the white matter to persistent susceptibility to recurrent ischemia. Our approach is a significant departure from previous studies in that we will employ the full spectrum of developmental markers of the OL lineage and other neural cell types previously characterized by us in developing human white matter to define cellular mechanisms of chronic myelination failure. We will develop the first large animal model that permits an integrated quantitative regional and temporal histopathological analysis of the progression of white and gray matter injury with the application of EEG, MRI and quantitative cerebral blood flow studies. Upon completion of this project, we expect to gain fundamental new insights into pathogenetic mechanisms that trigger a failure of normal myelination in chronic PWMI. Our long-term objectives are to utilize this pre-clinical model to test new translational strategies to restore normal myelination and, potentially, neurological function in survivors of premature birth.
| Srivastava, Taasin; Diba, Parham; Dean, Justin M et al. (2018) A TLR/AKT/FoxO3 immune tolerance-like pathway disrupts the repair capacity of oligodendrocyte progenitors. J Clin Invest 128:2025-2041 |
| Back, Stephen A (2017) White matter injury in the preterm infant: pathology and mechanisms. Acta Neuropathol 134:331-349 |
| McClendon, Evelyn; Shaver, Daniel C; Degener-O'Brien, Kiera et al. (2017) Transient Hypoxemia Chronically Disrupts Maturation of Preterm Fetal Ovine Subplate Neuron Arborization and Activity. J Neurosci 37:11912-11929 |
| Penn, Anna A; Gressens, Pierre; Fleiss, Bobbi et al. (2016) Controversies in preterm brain injury. Neurobiol Dis 92:90-101 |
| Sherman, Larry S; Matsumoto, Steven; Su, Weiping et al. (2015) Hyaluronan Synthesis, Catabolism, and Signaling in Neurodegenerative Diseases. Int J Cell Biol 2015:368584 |
| Back, Stephen A (2015) Brain Injury in the Preterm Infant: New Horizons for Pathogenesis and Prevention. Pediatr Neurol 53:185-92 |
| Back, Stephen A; Rosenberg, Paul A (2014) Pathophysiology of glia in perinatal white matter injury. Glia 62:1790-815 |
| Hagen, Matthew W; Riddle, Art; McClendon, Evelyn et al. (2014) Role of recurrent hypoxia-ischemia in preterm white matter injury severity. PLoS One 9:e112800 |
| Drobyshevsky, Alexander; Jiang, Rugang; Lin, Laixiang et al. (2014) Unmyelinated axon loss with postnatal hypertonia after fetal hypoxia. Ann Neurol 75:533-41 |
| Dean, Justin M; Bennet, Laura; Back, Stephen A et al. (2014) What brakes the preterm brain? An arresting story. Pediatr Res 75:227-33 |
Showing the most recent 10 out of 31 publications
