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      Hydrogen sulfide-modified extracellular vesicles from mesenchymal stem cells for treatment of hypoxic-ischemic brain injury.

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          Abstract

          We previously reported that preconditioning of mesenchymal stem cells (MSCs) with hydrogen sulfide (H2S) improved their therapeutic potential in cerebral ischemia. However, the mechanisms involved with this effect have not been determined. As one approach to address this issue, we focused on a neuroprotective role of modification of MSCs-derived extracellular vesicles (EVs) with H2S treatment, and further examined the underlying mechanisms during hypoxia-ischemia (HI) injury in neonatal mice. At 24 h following HI insult, neonatal mice received either systemically administered EVs (derived from MSCs) or H2S-EVs (derived from NaHS-preconditioned MSCs). Both treatments reached the injured region of the ipsilateral hemisphere within 2 h after administration and were incorporated into microglia and neurons. Mice receiving H2S-EVs exhibited substantially lower amounts of brain tissue loss, decreased levels of pro-inflammatory mediators, and a skewed distribution of CD45low microglia and CD45high brain mononuclear phagocytes toward a more anti-inflammatory condition as compared with that in mice receiving only EVs. Moreover, these neuroprotective and anti-inflammatory effects of H2S-EVs were accompanied with long-term preservation of cognitive and memory functions, in contrast to the functional deficits observed in mice receiving only EVs. This H2S preconditioning upregulated miR-7b-5p levels in EVs as determined with next-generation sequencing, while knockdown analyses revealed that inducing miR-7b-5p expression and targeting FOS in the ipsilateral cortex were essential for the neuroprotective and anti-inflammatory effects of H2S-EVs following HI exposure. Taken together, these results demonstrate that miR-7b-5p transferred by H2S-EVs into the ipsilateral hemisphere further induced miR-7b-5p expression, which promoted CD45low microglia and CD45high brain mononuclear phagocytes toward a beneficial phenotype and improved HI-induced cognitive impairments in neonatal mice.

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          Author and article information

          Journal
          J Control Release
          Journal of controlled release : official journal of the Controlled Release Society
          Elsevier BV
          1873-4995
          0168-3659
          December 10 2020
          : 328
          Affiliations
          [1 ] Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China.
          [2 ] Department of Medical Psychology and Ethics, School of Basic Medicine Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, PR China.
          [3 ] Department of Neurosurgery, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Jinan, Shandong 250012, PR China.
          [4 ] Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China. Electronic address: wangzhen@sdu.edu.cn.
          Article
          S0168-3659(20)30478-8
          10.1016/j.jconrel.2020.08.037
          32858071
          f5990774-a077-4f0c-8d7e-efaa79a597aa
          History

          Extracellular vesicles,Hypoxia-ischemia,H(2)S,miR-7b-5p,Microglia polarization

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