Modeling Neural Stem Cell Dynamics in Congenital Heart Disease

Porter, Demisha Donei Lasha

Modeling Neural Stem Cell Dynamics in Congenital Heart Disease

dc.contributor.author	Porter, Demisha Donei Lasha	en
dc.contributor.committeechair	Morton, Paul D.	en
dc.contributor.committeemember	Theus, Michelle H.	en
dc.contributor.committeemember	Pickrell, Alicia M.	en
dc.contributor.committeemember	Buczynski, Matthew	en
dc.contributor.department	Graduate School	en
dc.date.accessioned	2023-06-29T08:01:10Z	en
dc.date.available	2023-06-29T08:01:10Z	en
dc.date.issued	2023-06-28	en
dc.description.abstract	Neural stem/progenitor cells (NSPCs) play a crucial part in the evolutionary development of the human neocortex. During early postnatal development, NSPCs give rise to immature neurons called neuroblasts within the subventricular zone (SVZ) that utilize unique migratory streams to integrate widely in the cerebral cortex. However, the cellular mechanisms enabling these unique migratory routes through the compacted cellular landscape remain unknown. Special emphasis has been placed on understanding the susceptibility of these brain regions to severe conditions such as congenital heart disease (CHD), resulting in poor neurological outcomes. Owing to its reminiscent complexity to humans, the neonatal piglet (Sus scrofa domesticus), which possesses a highly evolved gyrencephalic neocortex and an expansive outer SVZ, provides a powerful translational model system for the study of how heart dysfunction impacts cortical development from both a modern and evolutionary perspective. The present study provides a detailed characterization of neuroblast migration along their associate substrates in the piglet cortex under normal physiological conditions and how reduced oxygenation (i.e., hypoxia) can impact their vulnerability and/or resistance to injury during a critical period of postnatal development. In this thesis, I investigated the spatiotemporal distribution and developmental origin of SVZ-derived neuroblasts. Following BrdU tracing, multiplex labeling, and confocal microscopy, I show that the porcine brain contains populations of newly generated (BrdU+/DCX+) neurons in the prefrontal cortex that are produced postnatally. Regional analyses using immunohistochemical staining for doublecortin (DCX), a marker expressed by immature neurons, revealed that DCX+ clusters co-express markers of neuronal cell migration (PSA-NCAM), GABAergic interneuron marker (GABA+), and specific transcription factors (SCGN+SP8+) associated with the caudal- and lateral ganglionic eminence progenitor domains in the ventral forebrain. Moreover, I found that DCX+ neuroblasts are encased by astrocytic processes and tightly associated with blood vessels in the SVZ. Additionally, this thesis describes the use of chronic hypoxia as a model to profile neuroblast migration along associated substrates in pathological conditions related to CHD. Together, this work serves as a framework for the functional utilization of the neonatal piglet to understand the impact of substrate-dependent neuronal migration on brain maturation and neurodevelopmental diseases.	en
dc.description.abstractgeneral	Congenital heart disease (CHD) remains a significant cause of abnormal fetal brain development, affecting 1-2% of live births per year. Although many surgical strategies have shown promise in increasing quality of life, the current challenges remain the long-term cognitive deficits and diverse neurodevelopmental disabilities due to CHD. Recent studies suggest that dysregulated neurogenesis, which is associated with impaired neocortical development in human fetuses of CHD, may be influenced by altered brain circulation of blood and oxygen deliverance during critical periods of prenatal cortical growth. The brain's subventricular zone (SVZ) niche is essential for producing new neurons following birth to restore, repair, and replace existing neurons in the developing brain. In addition, these newborn neurons undergo long-distance migration from the SVZ to reach their final cortical destinations and ultimately contribute to brain development/plasticity. This study seeks to characterize the migration patterns of newborn neurons and the substrates (e.g., blood vessels or astrocytes), enabling the movement along the unique migratory routes under normal and pathological (i.e., hypoxia) conditions. In short, we found that the vast majority of the SVZ-derived newborn neurons are inhibitory neurons (i.e., interneurons) that originate in the deep region of the brain called the telencephalon and migrate tangentially utilizing blood vessels as scaffolds to the cortex, which is likely to contribute to cortical plasticity. These postnatal piglet findings demonstrate that swine represent a powerful translational model system to study large-brained mammalian cortical development and neuronal migration as it correlates to humans in normal and diseased states.	en
dc.description.degree	Doctor of Philosophy	en
dc.format.medium	ETD	en
dc.identifier.other	vt_gsexam:37533	en
dc.identifier.uri	http://hdl.handle.net/10919/115573	en
dc.language.iso	en	en
dc.publisher	Virginia Tech	en
dc.rights	In Copyright	en
dc.rights.uri	http://rightsstatements.org/vocab/InC/1.0/	en
dc.subject	Human brain	en
dc.subject	Neurogenesis	en
dc.subject	Cell Migration	en
dc.subject	Subventricular Zone	en
dc.subject	Neuroblast	en
dc.subject	Neocortex	en
dc.title	Modeling Neural Stem Cell Dynamics in Congenital Heart Disease	en
dc.type	Dissertation	en
thesis.degree.discipline	Translational Biology, Medicine and Health	en
thesis.degree.grantor	Virginia Polytechnic Institute and State University	en
thesis.degree.level	doctoral	en
thesis.degree.name	Doctor of Philosophy	en