Human Umbilical Cord Therapy Improves Long-Term Behavioral Outcomes Following Neonatal Hypoxic Ischemic Brain Injury.

Tayla R Penny,Nicole M Jones,Joohyung Lee,Graham Jenkin,Courtney A Mcdonald,Amy E Sutherland,Yen Pham,Jamie G Mihelakis,Suzanne L Miller,Madison C B Paton,Michael C Fahey

doi:10.3389/fphys.2019.00283

Tayla R Penny, Nicole M Jones + Show 9 more

Open Access

https://doi.org/10.3389/fphys.2019.00283

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Abstract

Background: Hypoxic ischemic (HI) insult in term babies at labor or birth can cause long-term neurodevelopmental disorders, including cerebral palsy (CP). The current standard treatment for term infants with hypoxic ischemic encephalopathy (HIE) is hypothermia. Because hypothermia is only partially effective, novel therapies are required to improve outcomes further. Human umbilical cord blood cells (UCB) are a rich source of stem and progenitor cells making them a potential treatment for neonatal HI brain injury. Recent clinical trials have shown that UCB therapy is a safe and efficacious treatment for confirmed cerebral palsy. In this study, we assessed whether early administration of UCB to the neonate could improve long-term behavioral outcomes and promote brain repair following neonatal HI brain injury.Methods: HI brain injury was induced in postnatal day (PND) 7 rat pups via permanent ligation of the left carotid artery, followed by a 90 min hypoxic challenge. UCB was administered intraperitoneally on PND 8. Behavioral tests, including negative geotaxis, forelimb preference and open field test, were performed on PND 14, 30, and 50, following brains were collected for assessment of neuropathology.Results: Neonatal HI resulted in decreased brain weight, cerebral tissue loss and apoptosis in the somatosensory cortex, as well as compromised behavioral outcomes. UCB administration following HI improved short and long-term behavioral outcomes but did not reduce long-term histological evidence of brain injury compared to HI alone. In addition, UCB following HI increased microglia activation in the somatosensory cortex compared to HI alone.Conclusion: Administration of a single dose of UCB cells 24 h after HI injury improves behavior, however, a single dose of cells does not modulate pathological evidence of long-term brain injury.

Highlights

Neonatal brain injury underlies long-term neurological deficits, including cerebral palsy (CP) and other cognitive and behavioral deficits that may become apparent months to years after birth (Vannucci, 2000; Ferrari et al, 2010)
In order to ascertain the long term and overall behavioral burden, a long-term composite behavior score was calculated by combining data from D30 and D50 behavioral tests (Figure 1D) and an overall behavioral burden score was calculated by combining each of the individual test Z-scores for all behavioral tests (Figure 1E)
Our results demonstrate that there was an overall improvement in long-term behavioral outcomes following umbilical cord blood cells (UCB) administration, but this was not reflected in improvement in brain pathology, it didn’t exacerbate the injury compared to HI

Summary

Introduction

Neonatal brain injury underlies long-term neurological deficits, including cerebral palsy (CP) and other cognitive and behavioral deficits that may become apparent months to years after birth (Vannucci, 2000; Ferrari et al, 2010). The only treatment for HIE is therapeutic hypothermia which is effective and restricted in scope (Cerio et al, 2013) in that treatment needs to commence within 6 h of birth (Chiang et al, 2017), is best applied in well-equipped tertiary hospitals, and is not a suitable treatment for babies born preterm (Bennet et al, 2012). We assessed whether early administration of UCB to the neonate could improve long-term behavioral outcomes and promote brain repair following neonatal HI brain injury

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