Highlighting the Potential of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Alleviating Hypoxic-Ischemic Encephalopathy: Reshaping the Post-HI Milieu

Abstract

Hypoxic-ischemic encephalopathy (HIE) has severe long-term neurodevelopmental consequences that affect 1,5 out of 1000 term-liveborn neonates worldwide. HIE arises due to perinatal deprivation of glucose and oxygen of the neonate’s brain resulting in neuronal cell death and is characterized by distinct phases: primary energy failure, a latent period, secondary energy failure, and a tertiary injury process. The tertiary injury process is mainly responsible for permanent brain damage. Endogenous neurogenesis is initialized following HI, but the neonatal brain is incapable to maintain long-term neurogenesis, eventually failing to recover from HIE. Neurogenesis takes places in the subgranular zone and subventricular zone (SVZ) driven by neurotrophic factors. HI triggers perturbations in the SVZ that adapts its proliferative character and the cell fate of resident cells. A dominant glial cell fate following HI partially explains the incapability to endogenously recover from HIE. Hypothermia is the current standard clinical practice for HIE. The limited therapeutical window of 6 hours and efficiency of 50% of hypothermia calls for an alternative therapy. Intranasal (i.n.) administration of mesenchymal stem cells (MSCs) is a non-invasive therapy proofed to be effective in alleviating HIE in rodent models of HIE (i.e. the Rice-Vannucci model). MSCs do not integrate in the recipient’s tissue but exert their therapeutic effects in a paracrine manner through extracellular vesicles (EVs). Strikingly, the efficacy of alleviating HIE of intranasally administered MSC-derived EVs (MSC-EVs) versus whole MSCs is equal. MSC-EVs contain proteins, lipids, and RNA – including microRNAs. MSC-EV-microRNAs reduce neuronal apoptosis early in HIE. However, future research should further investigate the molecular constituents of MSC-EVs, mainly focusing on neurotrophic factors. To apply i.n. administration of MSC-EVs in the clinic, its therapeutical window and thereby the dosage quantity and frequency should be further defined. Thereby, MSC-EVs provide the potential to customize their cargo and to create cell-specific MSC-EVs.