Korean researchers at Sungkyunkwan University (SKKU) in Seoul have demonstrated that regenerative medicine using multipotent mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) could mitigate intraventricular hemorrhage-induced brain damage in newborn rats.
Reported in the December 15, 2020, edition of Stem Cells Translational Medicine, the study also identified an MSC-derived brain-derived neurotrophic factor (BNDF), which might lead to the development of the first safe and effective stem cell-based treatment of intraventricular hemorrhage in humans.
Although intraventricular hemorrhage can occur at any age, it is most common in premature babies, predominantly those born more than 10 weeks premature. Respiratory distress syndrome, unstable blood pressure or other medical conditions at birth further increase the risk of hemorrhage in such preemies.
Post-hemorrhagic hydrocephalus due to severe intraventricular hemorrhage can result in serious brain damage, including seizures, cerebral palsy, developmental retardation and increased mortality. For now, there are no safe and effective intraventricular hemorrhage treatments available.
"We believe that ours is the first study showing that MSC-derived EVs could reproduce the therapeutic efficacy of parent MSCs in attenuating severe [hemorrhage]-induced brain damage," said study leader Won Soon Park, a professor of pediatrics in the Samsung Medical Center at SKKU.
Importantly, the study established that a protein-coding gene, BDNF, which is secreted by MSCs and transferred through EVs, may be the key factor underlying the mitigation of intraventricular hemorrhage-induced brain damage.
Recent studies have shown that MSC-derived EVs can safely recapitulate the therapeutic efficacy of parent MSCs in various neonatal disorders, including neonatal stroke and hypoxic-ischemic encephalopathy.
Moreover, MSC-derived EVs are a cell-free therapy, so avoid the problems associated with direct MSC transplantation, which include the potential for tumorigenesis and immune rejection.
"As this cell-free therapy can overcome the potential concerns and side effects associated with viable MSC transplantation, the use of MSC-derived EVs might be an alternative for live stem cell therapy" in severe cases of intraventricular hemorrhage, Park told BioWorld Science.
If this is indeed the case, it raises the question of "whether neuroprotection is related to protein transfer from EVs to the damaged host brain tissue," he noted.
To address this, the SKKU researchers applied MSCs, MSC-derived EVs with or without BDNF genetic knockdown, or fibroblast-derived EVs in vitro to rat neuronal cells that had previously been exposed to thrombin to induce cell death.
They then repeated this in vivo in 4-day-old rats by injecting blood into their brains to induce severe intraventricular hemorrhage, then treating them 2 days later by transplanting either MSCs or one of the EV groups, with untreated rat neonates used as controls.
The results of the different treatments were then assessed using serial magnetic resonance imaging (MRI) and negative geotaxis and rotarod functional behavioral testing at 1, 7 and 28 days after severe IVH induction.
MSCs and MSC-derived EVs, but not those from BDNF-knockdown MSCs or fibroblasts, were shown to significantly reduce both thrombin-induced neuronal cell death in vitro and severe IVH-induced brain injuries and inflammation in vivo in neonatal rats.
"These findings suggest that MSC-derived EVs are as effective as parental MSCs in attenuating severe intraventricular hemorrhage-induced brain injuries, and that this neuroprotection is primarily mediated by BDNF transfer via EVs," said Park.
Interestingly, in an earlier study, the SKKU research team had shown that supplementary recombinant human BDNF dose-dependently recovered the lost neuroprotective action of BDNF knockdown MSCs, from which the EVs used in the present study were derived.
"Within this context, the BDNF knockdown MSC-EV group in our present study might be rescued by adding BDNF supplementation although this awaits confirmation in further studies," Park said.
However, before such trials can commence, "we must first progress to establishing the optimal timing, route of administration and dosage of the MSC-derived EVs."