eprintid: 10116810 rev_number: 30 eprint_status: archive userid: 608 dir: disk0/10/11/68/10 datestamp: 2020-12-09 15:51:24 lastmod: 2022-08-18 08:51:40 status_changed: 2020-12-09 15:51:24 type: article metadata_visibility: show creators_name: Robertson, NJ creators_name: Meehan, C creators_name: Martinello, KA creators_name: Avdic-Belltheus, A creators_name: Boggini, T creators_name: Mutshiya, T creators_name: Lingam, I creators_name: Yang, Q creators_name: Sokolska, M creators_name: Charalambous, X creators_name: Bainbridge, A creators_name: Hristova, M creators_name: Kramer, BW creators_name: Golay, X creators_name: Weil, B creators_name: Lowdell, MW title: Human umbilical cord mesenchymal stromal cells as an adjunct therapy with therapeutic hypothermia in a piglet model of perinatal asphyxia ispublished: inpress subjects: RFH subjects: UCH divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F82 divisions: C10 divisions: D19 divisions: G98 divisions: D11 divisions: G12 divisions: G14 divisions: G15 note: © 2020 International Society for Cell & Gene Therapy. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) abstract: BACKGROUND: With therapeutic hypothermia (HT) for neonatal encephalopathy, disability rates are reduced, but not all babies benefit. Pre-clinical rodent studies suggest mesenchymal stromal cells (MSCs) augment HT protection. AIMS: The authors studied the efficacy of intravenous (IV) or intranasal (IN) human umbilical cord-derived MSCs (huMSCs) as adjunct therapy to HT in a piglet model. METHODS: A total of 17 newborn piglets underwent transient cerebral hypoxia-ischemia (HI) and were then randomized to (i) HT at 33.5°C 1-13 h after HI (n = 7), (ii) HT+IV huMSCs (30 × 106 cells) at 24 h and 48 h after HI (n = 5) or (iii) HT+IN huMSCs (30 × 106 cells) at 24 h and 48 h after HI (n = 5). Phosphorus-31 and hydrogen-1 magnetic resonance spectroscopy (MRS) was performed at 30 h and 72 h and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells and oligodendrocytes quantified. In two further piglets, 30 × 106 IN PKH-labeled huMSCs were administered. RESULTS: HI severity was similar between groups. Amplitude-integrated electroencephalogram (aEEG) recovery was more rapid for HT+IN huMSCs compared with HT from 25 h to 42 h and 49 h to 54 h (P ≤ 0.05). MRS phosphocreatine/inorganic phosphate was higher on day 2 in HT+IN huMSCs than HT (P = 0.035). Comparing HT+IN huMSCs with HT and HT+IV huMSCs, there were increased OLIG2 counts in hippocampus (P = 0.011 and 0.018, respectively), internal capsule (P = 0.013 and 0.037, respectively) and periventricular white matter (P = 0.15 for IN versus IV huMSCs). Reduced TUNEL-positive cells were seen in internal capsule with HT+IN huMSCs versus HT (P = 0.05). PKH-labeled huMSCs were detected in the brain 12 h after IN administration. CONCLUSIONS: After global HI, compared with HT alone, the authors saw beneficial effects of HT+IN huMSCs administered at 24 h and 48 h (30 × 106 cells/kg total dose) based on more rapid aEEG recovery, improved 31P MRS brain energy metabolism and increased oligodendrocyte survival at 72 h. date: 2020-11-28 date_type: published official_url: http://dx.doi.org/10.1016/j.jcyt.2020.10.005 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1833960 doi: 10.1016/j.jcyt.2020.10.005 pii: S1465-3249(20)30930-0 lyricists_name: Avdic-Belltheus, Adnan lyricists_name: Golay, Xavier lyricists_name: Hristova, Mariya lyricists_name: Lowdell, Mark lyricists_name: Robertson, Nicola lyricists_name: Sokolska, Magdalena lyricists_name: Weil, Benjamin lyricists_id: AAVDI39 lyricists_id: XGOLA94 lyricists_id: MHRIS00 lyricists_id: MWLOW91 lyricists_id: NROBE79 lyricists_id: MSOKO71 lyricists_id: BWEIL09 actors_name: Austen, Jennifer actors_id: JAUST66 actors_role: owner full_text_status: public publication: Cytotherapy event_location: England citation: Robertson, NJ; Meehan, C; Martinello, KA; Avdic-Belltheus, A; Boggini, T; Mutshiya, T; Lingam, I; ... Lowdell, MW; + view all <#> Robertson, NJ; Meehan, C; Martinello, KA; Avdic-Belltheus, A; Boggini, T; Mutshiya, T; Lingam, I; Yang, Q; Sokolska, M; Charalambous, X; Bainbridge, A; Hristova, M; Kramer, BW; Golay, X; Weil, B; Lowdell, MW; - view fewer <#> (2020) Human umbilical cord mesenchymal stromal cells as an adjunct therapy with therapeutic hypothermia in a piglet model of perinatal asphyxia. Cytotherapy 10.1016/j.jcyt.2020.10.005 <https://doi.org/10.1016/j.jcyt.2020.10.005>. (In press). Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10116810/1/1-s2.0-S1465324920309300-main.pdf