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Small extracellular vesicles obtained from hypoxic mesenchymal stromal cells induce ischemic stroke recovery, cerebral angiogenesis and anti-inflammation in young and aged mice
We have previously shown that small extracellular vesicles (sEVs) obtained from mesenchymal stromal cells (MSCs) improve poststroke neurological recovery and that MSC-sEVs induce ischemic neuroprotection by modulating the brain infiltration of leukocytes and specifically polymorphonuclear neutrophils (PMNs) in young mice. Since sEVs from MSCs cultured under hypoxic conditions have been demonstrated to exhibit enhanced vasculature-related protection and pro-angiogenic effects by us and others and cerebral microvascular remodeling is essential for stroke recovery, we herein evaluated the effects of sEVs from hypoxic MSCs in human cerebral microvascular endothelial cells (hCMEC/D3) in vitro assays and in young mice exposed to intraluminal middle cerebral artery occlusion (MCAO), as well as the underlying mechanisms. We further evaluated the therapeutic efficacy of MSC-sEVs in aged mice that have not been studied so far. To study the microvascular actions of MSC-sEVs, young (8-10 weeks) male C57Bl6/j mice were exposed to intraluminal MCAO. Vehicle or sEVs (equivalent of 2×106 MSCs) obtained from cell culture media (sEVplatelet) or from MSCs cultured under ‘normoxic’ (21% O2; sEVnormoxic) or hypoxic (1% O2; sEVhypoxic) conditions were intravenously administered on days 1, 3, and 5 after ischemia. Neurological deficits, brain injury, neuronal survival, and microvascular characteristics were evaluated by Clark score, immunohistochemistry or 3D light sheet fluorescence microscopy (LSFM) over up to 56 days. In vitro, proliferation, migration, and tube formation of hCMEC/D3 were evaluated after vehicle or sEV treatment. To study the efficacy of MSC-sEVs in aged mice, young (8–10-week-old) and aged (15–24-month-old) male and female C57Bl6/j mice were exposed to intraluminal MCAO. After reperfusion or with 6 hours delay, vehicle or MSC-sEV preparations (equivalent of 2×106 MSCs) were intravenously administered. Neurological deficits, ischemic injury, blood-brain barrier (BBB) integrity, brain leukocyte infiltration, and ...
Small extracellular vesicles obtained from hypoxic mesenchymal stromal cells induce ischemic stroke recovery, cerebral angiogenesis and anti-inflammation in young and aged mice
We have previously shown that small extracellular vesicles (sEVs) obtained from mesenchymal stromal cells (MSCs) improve poststroke neurological recovery and that MSC-sEVs induce ischemic neuroprotection by modulating the brain infiltration of leukocytes and specifically polymorphonuclear neutrophils (PMNs) in young mice. Since sEVs from MSCs cultured under hypoxic conditions have been demonstrated to exhibit enhanced vasculature-related protection and pro-angiogenic effects by us and others and cerebral microvascular remodeling is essential for stroke recovery, we herein evaluated the effects of sEVs from hypoxic MSCs in human cerebral microvascular endothelial cells (hCMEC/D3) in vitro assays and in young mice exposed to intraluminal middle cerebral artery occlusion (MCAO), as well as the underlying mechanisms. We further evaluated the therapeutic efficacy of MSC-sEVs in aged mice that have not been studied so far. To study the microvascular actions of MSC-sEVs, young (8-10 weeks) male C57Bl6/j mice were exposed to intraluminal MCAO. Vehicle or sEVs (equivalent of 2×106 MSCs) obtained from cell culture media (sEVplatelet) or from MSCs cultured under ‘normoxic’ (21% O2; sEVnormoxic) or hypoxic (1% O2; sEVhypoxic) conditions were intravenously administered on days 1, 3, and 5 after ischemia. Neurological deficits, brain injury, neuronal survival, and microvascular characteristics were evaluated by Clark score, immunohistochemistry or 3D light sheet fluorescence microscopy (LSFM) over up to 56 days. In vitro, proliferation, migration, and tube formation of hCMEC/D3 were evaluated after vehicle or sEV treatment. To study the efficacy of MSC-sEVs in aged mice, young (8–10-week-old) and aged (15–24-month-old) male and female C57Bl6/j mice were exposed to intraluminal MCAO. After reperfusion or with 6 hours delay, vehicle or MSC-sEV preparations (equivalent of 2×106 MSCs) were intravenously administered. Neurological deficits, ischemic injury, blood-brain barrier (BBB) integrity, brain leukocyte infiltration, and ...
Small extracellular vesicles obtained from hypoxic mesenchymal stromal cells induce ischemic stroke recovery, cerebral angiogenesis and anti-inflammation in young and aged mice
Wang, Chen (Autor:in) / Hermann, Dirk
05.08.2022
Hochschulschrift
Elektronische Ressource
Englisch
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