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Preconditioning with hypoxic conditions has shown promise in enhancing the mesenchymal stem cells (MSCs)\u2019 reparative capabilities of the central nervous system. Recent evidence suggests that oxygen concentration and exposure duration can shape MSCs\u2019 phenotypes, supporting the need for further optimization of this strategy in a way to achieve maximal repair.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Wistar Han rat pups from both sexes underwent hypoxic-ischemic (HIE) brain injury at postnatal day 10 using the Rice-Vannucci model and were treated with umbilical cord derived-MSCs (UC-MSCs) preconditioned with prolonged mild hypoxia (MH; 5% oxygen for 48\u00a0h) or short severe hypoxia (SSH; 0.1% oxygen for 24\u00a0h) two days later.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our results show that UC-MSCs\u2019 were able to alleviate motor and cognitive deficits caused by the HI brain lesion. 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 na\u00efve 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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 hypoxic-ischemic brain injury.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s12015-026-11089-6","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T21:11:20Z","timestamp":1774905080000},"page":"1974-2000","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Quieting the Storm: Hypoxia as a Strategy to Boost UC-MSC Therapies for Hypoxic-Ischemic Brain Lesions in Neonatal Rats"],"prefix":"10.1007","volume":"22","author":[{"given":"In\u00eas","family":"Serrenho","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Mendes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00eas","family":"Caramelo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla M. 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