Human umbilical cord mesenchymal stromal cells as an adjunct therapy with therapeutic hypothermia in a piglet model of perinatal asphyxia.

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.

• Authors: Nicola J Robertson, Christopher Meehan, Kathryn A Martinello, Adnan Avdic-Belltheus, Tiziana Boggini, Tatenda Mutshiya, Ingran Lingam, Qin Yang, Magdalena Sokolska, Xenia Charalambous, Alan Bainbridge, Mariya Hristova, Boris W Kramer, Xavier Golay, Ben Weil, Mark W Lowdell
• Journal: Cytotherapy (Cytotherapy) Vol. 23 Issue 6 Pg. 521-535 (06 2021) ISSN: 1477-2566 [Electronic] England
• PMID: 33262073 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.

Topics

• Animals
• Humans
• Animals, Newborn
• Asphyxia (therapy)
• Disease Models, Animal
• Hypothermia, Induced
• Mesenchymal Stem Cells
• Swine
• Umbilical Cord