School of Medicine and Health Sciences Poster Presentations

Title

Hypoxia Results in White Matter Immaturity in a Piglet Model of Congenital Heart Disease

Poster Number

267

Document Type

Poster

Publication Date

3-2016

Abstract

Congenital heart disease (CHD) is the leading birth defect, affecting almost 1% of births each year. Full-term infants with CHD display subnormal brain development, underlying impairments in fine/gross motor skills, language, and memory. CHD infants have a high incidence of brain injury; partly due to insufficiencies in cerebral oxygen delivery in utero. Diffusion tensor imaging (DTI) studies have revealed that white matter (WM) immaturity is common in infants with CHD. Due to technical and ethical difficulties, the effects of CHD-induced brain injury on the cellular level remain elusive. To emulate insufficient cerebral oxygenation in CHD, we developed a porcine chronic hypoxia model and analyzed the microstructural and cellular effects of CHD on/in the corpus callosum (CC) with DTI and immunohistochemistry, respectively. Fixed porcine brains were imaged with a 3T-magnet at Johns Hopkins University. The cerebrum was isolated from DTI images using ROI Editor and fiber tracking was performed using DTI Studio. The primary antibodies used were PDGFR-α to label oligodendrocyte (OL) progenitors, CC1 to label mature OLs, Casp3 to label apoptotic cells, and Ki67 to label proliferating cells. To ensure an unbiased assessment, cell counts were performed using Stereology. DTI analysis demonstrated that hypoxia leads to a global reduction in the number and length of WM fiber tracts along with a decrease in fractional anisotropy-a metric of WM integrity and maturity. Immunohistochemical analyses revealed a 75% decrease in the density of apoptotic mature OLs and an 85% decrease in the density of proliferating OL progenitors in the CC following hypoxia (p<0.05). Together, these findings indicate an OL lineage-specific vulnerability to hypoxic exposure where OL progenitors fail to generate new OLs at a rate necessary for normal brain development. Hence, therapies aimed at restoring the regenerative capacity of resident OL progenitors within the CC offer promising avenues to improving neurological outcomes in the growing CHD population.

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Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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Presented at: GW Research Days 2016

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Hypoxia Results in White Matter Immaturity in a Piglet Model of Congenital Heart Disease

Congenital heart disease (CHD) is the leading birth defect, affecting almost 1% of births each year. Full-term infants with CHD display subnormal brain development, underlying impairments in fine/gross motor skills, language, and memory. CHD infants have a high incidence of brain injury; partly due to insufficiencies in cerebral oxygen delivery in utero. Diffusion tensor imaging (DTI) studies have revealed that white matter (WM) immaturity is common in infants with CHD. Due to technical and ethical difficulties, the effects of CHD-induced brain injury on the cellular level remain elusive. To emulate insufficient cerebral oxygenation in CHD, we developed a porcine chronic hypoxia model and analyzed the microstructural and cellular effects of CHD on/in the corpus callosum (CC) with DTI and immunohistochemistry, respectively. Fixed porcine brains were imaged with a 3T-magnet at Johns Hopkins University. The cerebrum was isolated from DTI images using ROI Editor and fiber tracking was performed using DTI Studio. The primary antibodies used were PDGFR-α to label oligodendrocyte (OL) progenitors, CC1 to label mature OLs, Casp3 to label apoptotic cells, and Ki67 to label proliferating cells. To ensure an unbiased assessment, cell counts were performed using Stereology. DTI analysis demonstrated that hypoxia leads to a global reduction in the number and length of WM fiber tracts along with a decrease in fractional anisotropy-a metric of WM integrity and maturity. Immunohistochemical analyses revealed a 75% decrease in the density of apoptotic mature OLs and an 85% decrease in the density of proliferating OL progenitors in the CC following hypoxia (p<0.05). Together, these findings indicate an OL lineage-specific vulnerability to hypoxic exposure where OL progenitors fail to generate new OLs at a rate necessary for normal brain development. Hence, therapies aimed at restoring the regenerative capacity of resident OL progenitors within the CC offer promising avenues to improving neurological outcomes in the growing CHD population.