Abstract 19852: Depletion of Neurogenesis within Key Neural Stem/Progenitor Cell Pools Contributes to Brain Immaturity in Congenital Heart Disease

Abstract

Objectives: Congenital heart disease (CHD) often causes neurological deficits throughout life; primarily due to immature brain development as a consequence of restricted cerebral oxygenation during fetal life. However, the underlying cellular mechanisms remain poorly understood. The primary goal of this study is to model CHD-induced brain injury with a species similar to humans to better understand how the brain responds to these pathologies. Methods: Piglets were used in this study because their brains display highly evolved neocortexes. Newborn pigs were housed in a hypoxic (Hx) chamber (10.5% FiO2) for 11 days, alongside normoxic (Nx) controls. We used MRI to assess cortical folding and volume. Cell tracers (CTG) were injected into the subventricular zone (SVZ), prior to Hx exposure, to label neural stem/progenitor cells (NSPCs). t2* scans were acquired to visualize the migratory paths and destination of labeled cells. Immunostains determined the fate of labeled cells and the cellular composition of the cortex. Findings: Hx reduces cortical volume and folding (gyrification index) (Fig. 1a); a phenomenon commonly seen in CHD patients. The porcine SVZ shares significant anatomical/structural similarities to the human SVZ and a majority of NSPCs in the SVZ generate immature neurons that migrate to the frontal cortex where they mature into GABAergic (Calr+) interneurons. Hx reduces the capacity of neurogenesis (Sox2+Ki67+) within the SVZ and limits the contribution of SVZ-derived neurons (CTG+Dcx+) to postnatal cortical development (Fig. 1b). Finally, Hx reduces the number of immature (Dcx+) as well as mature interneurons (Calr+NeuN+) within the frontal cortex (Fig.1c). Conclusions: Immature brain development seen in CHD patients is due, in part, to a depletion of neuronal producing NSPCs in the SVZ. Therapies aimed at protecting these vulnerable cells or restoring neurogenic potential from the SVZ will likely improve neurological outcomes in CHD.