Mesenchymal Stem Cell (MSC)-Derived Extracellular Vesicles Protect from Neonatal Stroke by Interacting with Microglial Cells.
Praneeti PathipatiMatthieu LecuyerJoel FaustinoJacqueline StrivelliDonald G PhinneyZinaida S VexlerPublished in: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics (2021)
Mesenchymal stem cell (MSC)-based therapies are beneficial in models of perinatal stroke and hypoxia-ischemia. Mounting evidence suggests that in adult injury models, including stroke, MSC-derived small extracellular vesicles (MSC-sEV) contribute to the neuroprotective and regenerative effects of MSCs. Herein, we examined if MSC-sEV protect neonatal brain from stroke and if this effect is mediated via communication with microglia. MSC-sEV derived from bone marrow MSCs were characterized by size distribution (NanoSight™) and identity (protein markers). Studies in microglial cells isolated from the injured or contralateral cortex of postnatal day 9 (P9) mice subjected to a 3-h middle cerebral artery occlusion (tMCAO) and cultured (in vitro) revealed that uptake of fluorescently labeled MSC-sEV was significantly greater by microglia from the injured cortex vs. contralateral cortex. The cell-type-specific spatiotemporal distribution of MSC-sEV was also determined in vivo after tMCAO at P9. MSC-sEV administered at reperfusion, either by intracerebroventricular (ICV) or by intranasal (IN) routes, accumulated in the hemisphere ipsilateral to the occlusion, with differing spatial distribution 2 h, 18 h, and 72 h regardless of the administration route. By 72 h, MSC-sEV in the IN group was predominantly observed in Iba1+ cells with retracted processes and in GLUT1+ blood vessels in ischemic-reperfused regions. MSC-sEV presence in Iba1+ cells was sustained. MSC-sEV administration also significantly reduced injury volume 72 h after tMCAO in part via modulatory effects on microglial cells. Together, these data establish feasibility for MSC-sEV delivery to injured neonatal brain via a clinically relevant IN route, which affords protection during sub-acute injury phase.
Keyphrases
- induced apoptosis
- mesenchymal stem cells
- bone marrow
- cell cycle arrest
- cerebral ischemia
- atrial fibrillation
- middle cerebral artery
- neuropathic pain
- functional connectivity
- stem cells
- type diabetes
- lipopolysaccharide induced
- computed tomography
- endoplasmic reticulum stress
- pregnant women
- blood brain barrier
- adipose tissue
- heart failure
- white matter
- spinal cord
- spinal cord injury
- acute myocardial infarction
- small molecule
- multiple sclerosis
- insulin resistance
- single cell
- endothelial cells
- young adults
- acute respiratory distress syndrome
- respiratory failure
- ischemia reperfusion injury
- deep learning
- coronary artery disease
- positron emission tomography