Brain Tissue-Derived Extracellular Vesicle Mediated Therapy in the Neonatal Ischemic Brain.

Nam Phuong Nguyen,Elizabeth Nance,Najma Hashi,Ziming Ye,My-Anh Doan,Hawley Helmbrecht,Tolulope Adebayo

doi:10.3390/ijms23020620

Nam Phuong Nguyen, Elizabeth Nance + Show 5 more

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https://doi.org/10.3390/ijms23020620

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Abstract

Hypoxic-Ischemic Encephalopathy (HIE) in the brain is the leading cause of morbidity and mortality in neonates and can lead to irreparable tissue damage and cognition. Thus, investigating key mediators of the HI response to identify points of therapeutic intervention has significant clinical potential. Brain repair after HI requires highly coordinated injury responses mediated by cell-derived extracellular vesicles (EVs). Studies show that stem cell-derived EVs attenuate the injury response in ischemic models by releasing neuroprotective, neurogenic, and anti-inflammatory factors. In contrast to 2D cell cultures, we successfully isolated and characterized EVs from whole brain rat tissue (BEV) to study the therapeutic potential of endogenous EVs. We showed that BEVs decrease cytotoxicity in an ex vivo oxygen glucose deprivation (OGD) brain slice model of HI in a dose- and time-dependent manner. The minimum therapeutic dosage was determined to be 25 μg BEVs with a therapeutic application time window of 4–24 h post-injury. At this therapeutic dosage, BEV treatment increased anti-inflammatory cytokine expression. The morphology of microglia was also observed to shift from an amoeboid, inflammatory phenotype to a restorative, anti-inflammatory phenotype between 24–48 h of BEV exposure after OGD injury, indicating a shift in phenotype following BEV treatment. These results demonstrate the use of OWH brain slices to facilitate understanding of BEV activity and therapeutic potential in complex brain pathologies for treating neurological injury in neonates.

Highlights

Hypoxic-Ischemic Encephalopathy (HIE) is the leading cause of morbidity and mortality in neonates, to which there is no cure
IL-10 expression after brain tissue-derived EVs (BEVs) treatment is comparable to the healthy control, pointing to the role that BEVs play in regulating injury attenuation
As changes in microglial phenotypes are connected to inflammation, disease onset and progression, and stimuli from the local environment [45], we paired the gene expression analysis with phenotypic profiling of microglia to explore the role that BEVs play in an HI model

Summary

Introduction

Hypoxic-Ischemic Encephalopathy (HIE) is the leading cause of morbidity and mortality in neonates, to which there is no cure. HIE has worldwide impact, affecting 1–8 neonates for every 1000 live births in developed countries, and as high as 26 neonates for every 1000 live births in low resource countries [4–6]. This condition can cause long-term neurological disabilities such as cerebral palsy, epilepsy, and cognitive impairment if left untreated. Neonates with HIE are usually symptomatic shortly after delivery with abnormalities in posture, muscle movement, cognitive response, and seizures [7]. Complex risk factors such as in utero infection, antepartum bleeding, uterine rupture, and maternal socioeconomic standing make HIE difficult to predict and diagnose at the time of injury [8]

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