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Access to allogeneic sources of UCB cells offer the potential for early administration to optimise their therapeutic capacities. As preterm infants often require ventilatory support, which can contribute to preterm brain injury, we investigated the efficacy of early UCB cell administration following ventilation to reduce white matter inflammation and injury.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Preterm fetal sheep (0.85 gestation) were randomly allocated to no ventilation (SHAM; <jats:italic>n<\/jats:italic>\u2009=\u20095) or 15\u00a0min <jats:italic>ex utero<\/jats:italic> high tidal volume ventilation. One hour following ventilation, fetuses were randomly allocated to i.v. administration of saline (VENT; <jats:italic>n<\/jats:italic>\u2009=\u20097) or allogeneic term-derived UCB cells (24.5\u2009\u00b1\u20095.0\u00a0million cells\/kg; VENT\u2009+\u2009UCB; <jats:italic>n<\/jats:italic>\u2009=\u20097). Twenty-four hours after ventilation, lambs were delivered for magnetic resonance imaging and post-mortem brain tissue collected. Arterial plasma was collected throughout the experiment for cytokine analyses. To further investigate the results from the in vivo study, mononuclear cells (MNCs) isolated from human UCB were subjected to in vitro cytokine-spiked culture medium (TNF\u03b1 and\/or IFN\u03b3; 10 ng\/mL; <jats:italic>n<\/jats:italic>\u2009=\u20093\/group) for 16\u00a0h then supernatant and cells collected for protein and mRNA assessments respectively.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>In VENT\u2009+\u2009UCB lambs, systemic IFN\u03b3 levels increased and by 24\u00a0h, there was white matter neuroglial activation, vascular damage, reduced oligodendrocytes, and increased average, radial and mean diffusivity compared to VENT and SHAM. No evidence of white matter inflammation or injury was present in VENT lambs, except for mRNA downregulation of <jats:italic>OCLN<\/jats:italic> and <jats:italic>CLDN1<\/jats:italic> compared to SHAM. In vitro, MNCs subjected to TNF\u03b1 and\/or IFN\u03b3 displayed both pro- and anti-inflammatory characteristics indicated by changes in cytokine (IL-18 &amp; IL-10) and growth factor (BDNF &amp; VEGF) gene and protein expression compared to controls.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>UCB cells administered early after brief high tidal volume ventilation in preterm fetal sheep causes white matter injury, and the mechanisms underlying these changes are likely dysregulated responses of the UCB cells to the degree of injury\/inflammation already present. If immunomodulatory therapies such as UCB cells are to become a therapeutic strategy for preterm brain injury, especially after ventilation, our study suggests that the inflammatory state of the preterm infant should be considered when timing UCB cells administration.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12974-024-03053-3","type":"journal-article","created":{"date-parts":[[2024,5,8]],"date-time":"2024-05-08T05:02:19Z","timestamp":1715144539000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Early administration of umbilical cord blood cells following brief high tidal volume ventilation in preterm sheep: a cautionary tale"],"prefix":"10.1186","volume":"21","author":[{"given":"Nhi T.","family":"Tran","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tayla R.","family":"Penny","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyra YY.","family":"Chan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanya","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paris C.","family":"Papagianis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tara","family":"Sepehrizadeh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lakshmi","family":"Nekkanti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valerie A.","family":"Zahra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yen","family":"Pham","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tamara","family":"Yawno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilias","family":"Nitsos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharmony B.","family":"Kelly","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alison M.","family":"Thiel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"de Veer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dhafer M.","family":"Alahmari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael C.","family":"Fahey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Graham","family":"Jenkin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suzanne L.","family":"Miller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Galinsky","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Graeme R.","family":"Polglase","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Courtney A.","family":"McDonald","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,5,8]]},"reference":[{"key":"3053_CR1","volume-title":"Umbilical cord blood cells for Perinatal Brain Injury: the right cells at the right time? 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