Niche-specific microglia as key regulators of neural stem cell quiescence

• Autores: Pere Duart Abadia
• Directores de la Tesis: Isabel Fariñas Gomez (dir. tes.), Jose Manuel Morante Redolat (codir. tes.)
• Lectura: En la Universitat de València ( España ) en 2024
• Idioma: español
• Tribunal Calificador de la Tesis: Francisco Javier Vitorica Ferrández (presid.), Felipe Ortega (secret.), Ana Cristina Delgado Fumero (voc.)
• Programa de doctorado: Programa de Doctorado en Biomedicina y Biotecnología por la Universitat de València (Estudi General)
• Menciones:
  • Internacional
• Calificación: Sobresaliente Cum Laude
• Materias:
  • Ciencias de la vida
    • Biología celular
• Enlaces
  • Tesis en acceso abierto en: TESEO
• Resumen

  • Within most adult tissues, different populations of somatic stem cells (SCs) play a pivotal role in tissue maintenance and regeneration by carefully balancing the production of cell progeny and their own self-renewal. Regardless of the tissue dynamics, these somatic SCs deploy strategies to ensure the tissue long-term homeostasis, being one of the most critical and less understood, their ability to transit bidirectionally between an active proliferative state and a highly regulated quiescence. Within the adult mammalian brain, neural stem cells (NSCs), situated in the subependymal zone (SEZ), generate millions of neurons, contributing to the olfactory bulb circuits. The SEZ, lining the lateral ventricle wall, forms a specialized microenvironment where NSCs receive signals from the niche, orchestrating transitions among three recently identified distinct states: quiescent (qNSC), primed (pNSC), and activated (aNSC), each characterized by unique molecular identities. While the role of various niche elements in regulating NSC activation has been explored, the contribution of microglia in this context remains obscure and, at times, contentious. This thesis addresses these gaps and demonstrates by both in vitro and in vivo experimental sets, that microglia actively induce/sustain NSC quiescence. Additionally, this work reveals distinctive morphological and localization features that set SEZ microglia apart from those in other brain regions. We also unveil previously unrecognized transcriptomic heterogeneity in the adult SEZ microglia under homeostatic conditions. Specifically, our research identifies a microglial state, that we have named `niche-associated microglia or NAM, which shares similarities with diverse microglial types identified in different contexts, such as DAM or WAM. Notably, NAM closely interact with NSCs, emphasizing its crucial role in maintaining the quiescent state vital for NSC long-term viability. In the final phase of our investigation, using state-of-the art global transcriptomic techniques, we have explored the molecular landscape of microglial signals that could be mediating the observed pro-quiescence effect. Experimental validation of several of the identified candidate signals suggests a complex scenario where microglia might exert multiple and finely tuned effects on NSCs with an overall result leading to the induction/maintenance of NSCs. The results obtained in this thesis further advance our understanding of the intricate mechanisms governing adult stem cell quiescence in the SEZ microenvironment. Additionally, they shed light on the role of a long unaccounted niche component, specifically microglia.