Paracrine Regulation of the Neurogenic Niche by Neural Stem Cells

• Autor(a) principal: Oliveira, Raúl Portugal
• Data de Publicação: 2022
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10362/153499
• topic: Neural stem cells; Neurogenesis; Neurogenic niches; Paracrine regulation; Secretome; Domínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e Tecnologias

Studies on neural stem cells (NSCs) largely focus on their differentiation into neurons in the adult brain, a process known as adult neurogenesis. However, new evidence suggests NSCs also regulate their surroundings through paracrine signaling. Their location in the brain, close to the vasculature and the cerebrospinal fluid, places them in an ideal position to receive extrinsic cues from the environment and relay them to the members of the neurogenic niches. Here, we aimed to explore how metabolic regula- tors and insults influence the NSC conditioned media (CM) and its effects on three components of the niches: differentiating NSCs, microglia, and endothelial cells. NSCs were pre-conditioned with metabolic regulators—tauroursodeoxycholic acid, propionate, and an exercise-mimicking cocktail of growth factors—and the resulting secretomes (mitCMs) seemed to increase neuronal differentiation. NSCs pre-conditioned with CM from injured cells released a secre- tome (boosted CM) which seemed to promote neuronal differentiation and microglial phagocytosis. Contrastingly, the secretome of NSCs pre-conditioned with serum of depressed mice (uCMS CM) de- creased neuronal differentiation and microglial phagocytosis. No alterations in blood vessel formation by endothelial cells exposed to these CMs were detected. To understand how CMs trigger these changes, we analyzed their composition. MitCMs and boosted CM seemed to be enriched in metabolites involved in neuroprotection and metabolic remodeling, such as lactate and 3-methyl-2-oxovalerate. Boosted CM also appeared to be enriched in miRNAs involved in neurogenesis and microglial modulation, such as miRNA-21, miRNA-125b, and miRNA-424. Summarily, our findings highlight a new role for the paracrine regulation of the neurogenic niche by NSCs. In the context of increased metabolic activity, but also of injury, NSCs appear to release a neuroprotective secretome, modulating differentiating NSCs and microglia towards a neurogenesis-fa- voring phenotype. However, depression-associated factors induce the release of a neurogenesis-sup- pressing secretome, as it appears to decrease neuronal differentiation and microglial phagocytosis.