Mesenchymal-Stem-Cell-Derived Extracellular Vesicles Attenuate Brain Injury in Escherichia coli Meningitis in Newborn Rats

Abstract

We recently reported that transplantation of mesenchymal stem cells (MSCs) significantly reduced bacterial growth and brain injury in neonatal meningitis induced by Escherichia coli (E. coli) infection in newborn rats. As a next step, to verify whether the MSCs protect against brain injury in a paracrine manner, this study was designed to estimate the efficacy of MSC-derived extracellular vesicles (MSC-EVs) in E. coli meningitis in newborn rats. E. coli meningitis was induced without concomitant bacteremia by the intra-cerebroventricular injection of 5 × 102 colony-forming units of K1 (-) E. coli in rats, at postnatal day 11. MSC-EVs were intra-cerebroventricularly transplanted 6 h after the induction of meningitis, and antibiotics were administered for three consecutive days starting at 24 h after the induction of meningitis. The increase in bacterial growth in the cerebrospinal fluid measured at 24 h after the meningitis induction was not significantly reduced following MSC-EV transplantation. However, an increase in brain cell death, reactive gliosis, and inflammation following meningitis were significantly attenuated after MSC-EV transplantation. Taken together, our results indicate that MSCs show anti-apoptotic, anti-gliosis, and anti-inflammatory, but not antibacterial effects, in an EV-mediated paracrine manner in E. coli-induced neonatal meningitis.

A Review of the Use of Extracellular Vesicles in the Treatment of Neonatal Diseases: Current State and Problems with Translation to the Clinic

“…However, when the antibiotics were combined with MSC-EVs, the inflammation and subsequent brain damage were significantly reduced. This suggests that therapy based on MSC-EVs may offer a novel approach to the treatment of neonatal meningitis by utilizing the anti-inflammatory and immunomodulatory properties of MSC-EVs [ 190 ].…”

Reactive Gliosis in Neonatal Disorders: Friend or Foe for Neuroregeneration?

“…The extracellular vesicles used exclusively as clinical treatments for the modulation of neonatal astrogliosis could be manufactured as off-the-shelf medicine, also facilitating their application outside the neonatal intensive care unit (NICU). To date, the promising effectiveness of stromal/mesenchymal stem cell transplantation in governing neonatal astrogliosis has been demonstrated by many studies dedicated to perinatal asphyxia, intraventricular hemorrhages, and infections [169][170][171][172][173].…”

Extracellular Vesicles as a New Therapeutic Entity

“…MSC-derived EVs (MSC-EVs) are now well established as potential therapeutics due to their regenerative potential and immune modulation [ 3 , 7 , 8 , 9 , 10 , 11 ]. A research article reported a novel therapeutic effect of MSC-EVs on meningitis in newborn rats induced by Escherichia coli ( E. coli ) [ 12 ]. Intra-cerebroventricular transplantation of MSC-EVs attenuated brain cell death, reactive gliosis, and inflammation including the number of active microglia and the production of inflammatory cytokines, while there was no significant effect on bacterial growth.…”