Mesenchymal Stem Cell (MSC)–Derived Extracellular Vesicles Protect from Neonatal Stroke by Interacting with Microglial Cells

• Published in: Neurotherapeutics Vol. 18; no. 3; pp. 1939 - 1952
• Main Authors: Pathipati, Praneeti, Lecuyer, Matthieu, Faustino, Joel, Strivelli, Jacqueline, Phinney, Donald G., Vexler, Zinaida S.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-07-2021; Springer Nature B.V
• Subjects: Animals; Animals, Newborn; Biomedical and Life Sciences; Biomedicine; Blood vessels; Bone marrow; Cells, Cultured; Cerebral blood flow; Cortex; Extracellular vesicles; Extracellular Vesicles - metabolism; Extracellular Vesicles - transplantation; Female; Hypoxia; Ischemia; Male; Mesenchymal Stem Cell Transplantation - methods; Mesenchymal stem cells; Mesenchymal Stem Cells - metabolism; Mice; Mice, Inbred C57BL; Microglia; Microglia - metabolism; Microglial cells; Neonates; Neurobiology; Neurology; Neuroprotection; Neuroprotection - physiology; Neurosciences; Neurosurgery; Newborn babies; Original; Original Article; Reperfusion; Size distribution; Spatial distribution; Stem cells; Stroke; Stroke - metabolism; Stroke - prevention & control; Temporal distribution; Extracellular vesicles; Perinatal; Stroke; Microglia; Mesenchymal stem cells
• ISSN: 1933-7213; 1878-7479; 1878-7479
• DOI: 10.1007/s13311-021-01076-9

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.