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Serrenho, I.

Publications and source records attributed to Serrenho, I..

2 recordsLinked to original sources
bioRxiv2025

Quieting the Storm: Hypoxia as a Strategy to Boost UC-MSC Therapies for Neonatal Hypoxic-Ischemic Encephalopathy

Integrating stem cell therapies into clinical settings faces several challenges, particularly in achieving the high cell yields necessary for attaining therapeutic doses. Preconditioning with hypoxic conditions has shown promise in enhancing the UC-MSCs reparative capabilities of the central nervous system. Recent evidence suggests that oxygen concentration and exposure duration can shape MSCs phenotypes, supporting the need for further optimization of this strategy in a way to achieve maximal repair. In this study, we assessed the effects of both prolonged mild hypoxia (MH; 5% oxygen for 48 hours) and short severe hypoxia (SSH; 0.1% oxygen for 24 hours) on UC-MSCs ability to alleviate motor and cognitive deficits in a rodent model of neonatal HIE. Our results show that short, severe hypoxia led to more improvements in functional recovery than prolonged mild hypoxia, supporting that specific preconditioning parameters are crucial in maximizing UC-MSC therapeutic potential. To investigate the molecular effects of hypoxia-preconditioned MSCs in the neonatal brain post-HIE, we employed untargeted proteomics on ipsilesional brain samples from control, HIE, HIE treated with naive UC-MSCs, and HIE treated with SSH-preconditioned UC-MSCs groups, 30 days after lesion induction. This approach identified protein signatures related to injury and therapeutic intervention. Pathway enrichment analysis further revealed that administration of UC-MSCs preconditioned with short severe hypoxia significantly impacted neural signaling, protein synthesis, and energy metabolism pathways, pointing to long-term mechanisms that may support neuronal repair. These findings enhance our understanding of hypoxia-preconditioning in MSCs therapy in driving a positive therapeutic response, supporting the development of more effective and feasible treatments for neonatal HIE.

neuroscience↗
bioRxiv2025

Nose-to-Brain Healing: Hypoxia-Preconditioned Mesenchymal Stem Cells Prompt Recovery in Hypoxic-Ischemic Encephalopathy Rats

Neonatal HIE poses a significant risk factor for neurodevelopment impairment. Therapeutic hypothermia, the current standard of care for this condition, has several constraints and reduced effectivity, especially in more severe cases. Thus, it is necessary to explore novel therapeutics, like MSCs. Although previous studies report that administration of MSCs (from different sources) prompted the recovery of HIE-lesioned animals, high doses are currently used. First, this study compared the efficacy of IN versus IV administration of 50,000 UC-MSCs in a rat model of neonatal HI brain injury. For this cell dose, only IN-UC-MSC therapy reduced infarct volume, an effect accompanied by improvements of motor skills and recognition memory. Also, IN-UC-MSC administration restored myelination in the corpus callosum and mitigated glial reactivity more effectively than IV administration. In a second part of the study, to potentiate the effect of UC-MSCs administration, postnatal rats that underwent HI injury received 25,000 hypoxia-preconditioned UC-MSCs or its secretome two days later, via IN route. The administration of a low-dose of hypoxia-preconditioned UC-MSCs was sufficient to induce neurological recovery and modulation of glial response. Moreover, the administration of the secretome of these cells was enough to induce the same extent of recovery. These findings support the higher potential of IN-UC-MSC administration, compared to IV administration, while enhancing our understanding of hypoxia-preconditioning and the role of the MSCs secretome in driving a positive therapeutic response, contributing to the development of more effective and feasible treatments for neonatal HIE.

neuroscience↗