Umbilical cord blood therapy modulates neonatal hypoxic ischemic brain injury in both females and males

Tayla R Penny,Courtney A Mcdonald,Graham Jenkin,Suzanne L Miller,Joohyung Lee,Yen Pham,Michael C Fahey,Amy E Sutherland

doi:10.1038/s41598-021-95035-1

Tayla R Penny, Courtney A Mcdonald + Show 6 more

Open Access

https://doi.org/10.1038/s41598-021-95035-1

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Abstract

Preclinical and clinical studies have shown that sex is a significant risk factor for perinatal morbidity and mortality, with males being more susceptible to neonatal hypoxic ischemic (HI) brain injury. No study has investigated sexual dimorphism in the efficacy of umbilical cord blood (UCB) cell therapy. HI injury was induced in postnatal day 10 (PND10) rat pups using the Rice-Vannucci method of carotid artery ligation. Pups received 3 doses of UCB cells (PND11, 13, 20) and underwent behavioural testing. On PND50, brains were collected for immunohistochemical analysis. Behavioural and neuropathological outcomes were assessed for sex differences. HI brain injury resulted in a significant decrease in brain weight and increase in tissue loss in females and males. Females and males also exhibited significant cell death, region-specific neuron loss and long-term behavioural deficits. Females had significantly smaller brains overall compared to males and males had significantly reduced neuron numbers in the cortex compared to females. UCB administration improved multiple aspects of neuropathology and functional outcomes in males and females. Females and males both exhibited injury following HI. This is the first preclinical evidence that UCB is an appropriate treatment for neonatal brain injury in both female and male neonates.

Highlights

Preclinical and clinical studies have shown that sex is a significant risk factor for perinatal morbidity and mortality, with males being more susceptible to neonatal hypoxic ischemic (HI) brain injury
Following allocation to treatment groups, one pup died from the umbilical cord blood (UCB) group (1 female), and no pups died from the HI and Sham groups
Multiple comparisons show that males and females showed no difference between groups for both time to turn and time to walk up the angled board (Fig. 1a,b)

Summary

Introduction

Preclinical and clinical studies have shown that sex is a significant risk factor for perinatal morbidity and mortality, with males being more susceptible to neonatal hypoxic ischemic (HI) brain injury. Studies that have utilised the term-equivalent Rice-Vannucci rodent model of neonatal hypoxic ischemic (HI) brain injury[10] have shown that males and females both exhibit adverse neuropathologies and functional deficits in response to HI, but the mechanisms driving the progression of injury may differ and be sex specific[11]. Erythropoietin (EPO) is a neuroprotective therapy for neonates at clinical trial stage, and is more effective in reducing brain infarcts in females than males, and improving long-term sensorimotor function in a preclinical rodent model of stroke[33]. Given the potential for sex-specific effects, it is important to consider whether potential neuroprotective agents are effective in both males and females, to ensure effective clinical translation

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