Dissertation committee:
Σταματάκης Αντώνιος, Καθηγητής, Τμήμα Νοσηλευτικής, ΕΚΠΑ
Στυλιανοπούλου Φωτεινή, Ομότιμη Καθηγήτρια, Τμήμα Νοσηλευτικής, ΕΚΠΑ
Θωμαΐδου Δήμητρα, Διευθύντρια Ερευνών, Τμήμα Νευροβιολογίας, Ελληνικό Ινστιτούτο Παστέρ
Κιτράκη Ευθυμία Καθηγήτρια, Τμήμα Οδοντιατρικής, ΕΚΠΑ
Ευθυμιόπουλος Σπύρος, Καθηγητής, Τμήμα Βιολογικού, ΕΚΠΑ
Καζάνης Ηλίας, Επίκουρος Καθηγητής, Τμήμα Βιολογικού, Πανεπιστήμιο Πατρών
Luzzati Federico, Αναπληρωτής Καθηγητής, Τμήμα Επιστημών Ζωής και Βιολογίας Συστημάτων, Università degli Studi di Torino
Summary:
Within the adult mammalian brain, the prevailing consensus has long held that neural stem cells (NSCs) and precursor cells are confined to specific neurogenic domains. Recent research, however, has unveiled a phenomenon known as reactive neurogenesis, where brain injuries trigger the activation of NSCs, enhancing their potential to differentiate into various cell types and guiding their progeny to injured areas.Chemotherapy constitutes a form of brain chemical injury disrupting brain structure and function. Accumulating evidence highlights the detrimental effects of chemotherapeutic agents, which include reduced NSC proliferation, white matter damage, and neuroinflammation. Adult brain neurogenic niches, where NSCs reside, appear particularly vulnerable to chemotherapy, potentially contributing to the cognitive and emotional function deficits observed in cancer survivors. However, the brain's regenerative response to chemotherapy remains underexplored.To address this, we conducted targeted intraventricular infusions of the commonly used chemotherapeutic antimitotic agent Ara-C and assessed the different pathophysiological aspects of the imposed chemical damage in the two neurogenic niches, namely the Subventricular Zone of the lateral ventricles (SVZ) and the hippocampal Subgranular Zone (SGZ), and the surrounding brain parenchyma.First, our objective was to understand the changes within the cellular components of the subventricular zone (SVZ), a prominent neurogenic niche in the adult brain. This included examining the ependymal barrier and the lineage of NSCs, with a focus on their structural composition and dynamic characteristics. Second, we explored the impact of the chemical lesion on adjacent non-neurogenic regions, such as the striatum and corpus callosum, and their influence on the responses of the neurogenic niche. Our results revealed a loss of ependymal cell layer and long-term disruption of the dynamics of the NSC lineage within the SVZ niche. These niche alterations were accompanied by a vigorous and acute neuroinflammatory response, characterized by astrogliosis, microgliosis, and strong phagocytic activity both around the lateral walls and in the neighboring parenchyma. Apoptosis and tissue degeneration of brain structures adjacent to ventricular cavities also occurred.Moreover, we observed the infiltration of peripheral cells in the brain, with a specific population expressing Netrin-1, a molecule known for its role in axon guidance and implicated in axon regeneration. Notably, we reported a rerouting of neuroblasts from their normal SVZ - Olfactory Bulb migratory stream to the striatum, with distinct localization along striatal myelin tracts. These findings were accompanied by dysregulation in the oligodendrocyte lineage and myelin deficits, suggesting a possible connection of ectopic neuroblasts presence to the observed myelin defects. At the same time, newly born neurons lying in the vicinity of myelin tract gray matter acquired molecular phenotypes of region-specific mature neurons. Concurrently with dorsal SVZ ectopic migration, we noted an activation of NSCs of the ventral SVZ with migration towards the nucleus accumbens and anterior commissure. In parallel, we also examined the complex dynamics of the hippocampal neurogenic niche, which plays a crucial role in cognitive processes. Our data support the idea that Ara-C, in addition to affecting proliferation, severely impacted the dendritic development of neural progenitors, consequently leading to aberrant migration in the Dentate Gyrus of the hippocampus, pointing to a defective maturation process.Interestingly, we found that in both neurogenic niches, similar molecular cues related to neuroblast migration in the neurogenic niches under homeostatic conditions, are being altered in response to injury, underscoring their role in the underlying mechanisms.Overall, our analysis allowed us to shed light on the brain's adaptive responses to chemical injury and uncover adult neurogenesis-related alternative migration routes which get mobilized following brain injury, while it revealed the similarities and differences between the two neurogenic niches in their responses to injury.
