Journal
ACTA BIOMATERIALIA
Volume 113, Issue -, Pages 597-613Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.actbio.2020.06.037
Keywords
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Funding
- National Natural Science Foundation of China [81873768, 81671213]
- Key Research and Development Foundation of Shandong Province [2017GSF218091]
- National Key Research and Development Program of China [2017YFC0820203]
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Mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) (MSC-EVs) exhibit protective effects in damaged or diseased tissues. However, the role of EVs secreted by MSC in hypoxia-ischemic (HI) injury in neonatal mice remains unknown. Systemic administration of MSC-EVs attenuated acute brain damage and neuroinflammation, and skewed CD11b(+)/CD45(low) microglia and CD11b(+)/CD45(high) brain monocyte/macrophage towards a more anti-inflammatory property as determined at 72 h post-HI. In addition, MSC-EVs remarkably improve the injury outcomes pups prior to weaning (P21), while no effect on long-term memory impairment (P42). Importantly, these effects were preceded by incorporation of MSC-EVs into a large number of neurons and microglia within HI group. Abundant levels of miR-21a-5p were present in EVs as determined with next-generation sequencing. Notably, MSC-EVs treatment further increased miR-21a-5p levels at 72 h post HI. Knockdown analyses revealed that miR-21a-5p, and its target-Timp3, were essential for this neuroprotective property of MSC-EVs following HI exposure as demonstrated in both in vitro and in vivo models. These findings suggest that a systemic administration of EVs derived from MSC, have the capacity to incorporated into neurons and microglia where they can then exert neuroprotection against HI-induced injury in neonates through the delivery of miR-21a-5p. (C) 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
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