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.