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.
Highlights
Neonatal encephalopathy (NE) is an important cause of death and disability, affecting one to three out of 1000 births in the UK [1] and 10À25 out of 1000 births in Sub-Saharan Africa [2]
Stem cell pilot studies have been completed for NE, and clinical trials are underway for perinatal arterial ischemic stroke (50 million allogeneic bone marrow-derived mesenchymal stromal cells (MSCs) administered intranasally, NCT03356821) and bronchopulmonary dysplasia (30 million human umbilical cordderived MSCs (huMSCs)/ kg administered intratracheally, NCT03558334) [7]
Compared with HT, the standard therapy for babies with NE, there was a more rapid Amplitude-integrated electroencephalogram (aEEG) recovery beginning 25 h after HI and improved brain energy metabolism (31P magnetic resonance spectroscopy (MRS) PCr/Pi) on day 2 in the group given IN huMSCs at 24 h and 48 h with HT, no difference was seen in the Lac/NAA measures on 1H MRS
Summary
Neonatal encephalopathy (NE) is an important cause of death and disability, affecting one to three out of 1000 births in the UK [1] and 10À25 out of 1000 births in Sub-Saharan Africa [2]. After transplantation, MSCs “home” to the areas of injury [9] They do not survive long term or replace damaged tissues themselves but react to the needs of the environment by secreting growth factors and cytokines to regulate damage and repair, “auto-tuning” to the brain’s milieu [10]. These intrinsic adaptive properties of huMSCs make them excellent candidates to treat the devastating effects of NE. 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
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
