Neuroinflammation and neurological condition: a translation path toward regenerative medicine

Neuroinflammation is a complex pathological condition characterized by a wide range of cellular and molecular events involving peripheral inflammatory and immune cells, and various central nervous system (CNS) cells. We focused on its critical aspects in different conditions, such as traumatic injuries (spinal cord injury-SCI), immune-mediated inflammatory-demyelinating disorders (multiple sclerosis-MS), and neurodegenerative diseases. In this thesis work, we approached this complex issue trying to dissect specific aspects and questions in the path supporting the use of cellular therapies to control neuroinflammation. Firstly, we investigated how inflammation alters lipid microdomains and membrane fluidity in red blood cells and key cell types relevant to MS, including macrophages, neurons and oligodendrocyte precursor cells. Results show altered lipid compositions in these cells during inflammation, suggest that peripheral cell membrane lipids could serve as potential biomarkers. We also investigated the impact of different inflammatory stimuli on endothelial-to-mesenchymal transition (EndMT) in several endothelial cells, including brain endothelial cells. We found that inflammatory stimuli induce EndMT through the TGFβ pathway and it’s irreversible in our experimental condition. Subsequently, we investigated the variability of mesenchymal stromal cells (MSCs) used in cell therapies by characterizing the secretome of adipose-derived MSCs (adMSCs). We found substantial inter-donor variability in neuroprotective factors, which influenced the protective effect of adMSCs on neural-derived stem cells, suggesting the opportunity to introduce exclusion criteria among donors based on biological properties of MSCs. Lastly, we investigated the impact of altered extracellular matrix (ECM) environments in SCI on stem cell over time, revealing that ECM from the SCI acute phase significantly hinders cell viability and differentiation, whereas ECM from the chronic phase supports better stem cell differentiation and viability. The study emphasizes the importance of timing for effective cell-based therapies in SCI. Together, these studies contribute to the understanding of the multifaceted role of neuroinflammation in CNS pathology.