Neural Stem Cells Sensing Injury and Metabolic Stimuli Deliver Multiple Distinct Secretory Signals: Clues for Exercise-Induced Depression Relief

• Autor(a) principal: Silva, Francisca Maria Maravalhas Bento e
• Data de Publicação: 2023
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10362/162945
• topic: Depression; Metabolism; Neurogenic niche; Physical exercise; Secretome; Domínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e Tecnologias

Research into adult neural stem cells (NSCs) predominantly emphasizes their differentiation into neurons, a phenomenon referred to as adult neurogenesis. In addition, a decrease in adult neurogenesis has been associated with several neurological disorders, including Depression, while recent findings indicate that NSCs also exert influence on their environment via paracrine signaling. In fact, positioned near the vasculature and cerebrospinal fluid, NSCs reside in an ideal position to receive systemic cues from the environment to influence other cells within the neurogenic niches. Since mitochondria are strongly linked with NSC fate decisions and neurogenesis potential, we aim to understand the influence of mitochondrial metabolism on the therapeutic properties of NSC-derived secretome. In order to repli- cate the signals that NSC could potentially detect under pathological contexts, we subjected NSCs to various forms of stimuli. This involved exposing NSCs to insults such as the secretome of oxidative- damaged cells and serum obtained from depressed mice. Conversely, NSC conditioning approaches were also used to mimic the signals that NSCs might find in a healthy physiological context. For that, NSCs were pre-conditioned with mitochondrial metabolic regulators, including the microbial metabo- lite, propionate, and a blend of growth factors that mimic the effects of exercise in vitro. We found that metabolic boosters support the potential of NSC secretome to stimulate mitochondrial biogenesis in recipient differentiating cells, whereas Depression-associated signals significantly reduce this bioener- getic support. Additionally, when exposed to injury or metabolic pulses, such as physical exercise-as- sociated signals, NSCs seem to tailor their nanoparticle profile and extracellular content in neuroregen- erative microRNAs, to regulate neighboring cells in the niche. Lastly, in an animal model of Depression, physical exercise rescued the bioenergetic impairments observed in the neurogenic niches of these mice, crucial to induce NSC-driven neurogenesis. These insights translate into valuable knowledge to rethink novel non-invasive strategies to confer stress resilience and improve the life quality of people with cog- nitive impairments and major depressive disorder.