Intravenous (IV) infusion of bone marrow‐derived mesenchymal stem/stromal cells (MSCs) stabilizes the blood‐spinal cord barrier (BSCB) and improves functional recovery in experimental models of spinal cord injury (SCI). Although IV delivered MSCs do not traffic to the injury site, IV delivered small extracellular vesicles (sEVs) derived from MSCs (MSC‐sEVs) do and are taken up by a subset of M2 macrophages. To test whether sEVs released by MSCs are responsible for the therapeutic effects of MSCs, we tracked sEVs produced by IV delivered DiR‐labelled MSCs (DiR‐MSCs) after transplantation into SCI rats. We found that sEVs were released by MSCs in vivo, trafficked to the injury site, associated specifically with M2 macrophages and co‐localized with exosome markers. Furthermore, while a single MSC injection was sufficient to improve locomotor recovery, fractionated dosing of MSC‐sEVs over 3 days (F‐sEVs) was required to achieve similar therapeutic effects. Infusion of F‐sEVs mimicked the effects of single dose MSC infusion on multiple parameters including: increased expression of M2 macrophage markers, upregulation of transforming growth factor‐beta (TGF‐β), TGF‐β receptors and tight junction proteins, and reduction in BSCB permeability. These data suggest that release of sEVs by MSCs over time induces a cascade of cellular responses leading to improved functional recovery.

Background Intravenous infusion of mesenchymal stem cells (MSCs) derived from adult bone marrow improves behavioral function in rat stroke models. Rehabilitation therapy through physical exercise (Ex) also provides therapeutic efficacy for cerebral ischemia. Objective The purpose of this study was to investigate whether synergic effects of daily rehabilitation and intravenous infusion of MSCs has therapeutic effects after stroke in rats. Design This was an experimental study. Methods A permanent middle cerebral artery occlusion (MCAO) was induced by intraluminal vascular occlusion with a microfilament. Four experimental groups were studied: Group 1 (Vehicle only: Vehicle), Group 2 (Vehicle + exercise: Vehicle + Ex), Group 3 (MSCs only: MSCs) and Group 4 (MSCs + Ex: Combined). Rat MSCs were intravenously infused at 6 hours after MCAO and the rats received daily rehabilitation with treadmill running exercise for 20 min. Lesion size was assessed at 1, 14, 35 days using MR imaging. Functional outcome was assessed using the limb placement test. Results Both combined therapy and MSC infusion reduced lesion volume, induced synaptogenesis and elicited functional improvement compared with the groups without MSC infusion, but the effect was greater in the combined group. Limitations A limitation of this study is that the results were limited to an animal model and cannot be generalized to humans. Conclusions These data indicate that the combined therapy of daily rehabilitation and intravenous infusion of MSCs improved functional outcome in a rat MCAO model.

BACKGROUND:. Hyperperfusion syndrome (HPS) is a critical complication after carotid artery stenting (CAS) and carotid endarterectomy (CEA).OBJECTIVE:. T

OBJECTIVE: Reperfusion therapy with intravenous recombinant tissue plasminogen activator (rtPA) is the standard of care for acute ischemic stroke. However, hemorrhagic complications can result. Intravenous infusion of mesenchymal stem cells (MSCs) reduces stroke volume and improves behavioral function in experimental stroke models. One suggested therapeutic mechanism is inhibition of vascular endothelial dysfunction. The objective of this study was to determine whether MSCs suppress hemorrhagic events after rtPA therapy in the acute phase of transient middle cerebral artery occlusion (tMCAO) in rats.METHODS: After induction of tMCAO, 4 groups were studied: 1) normal saline [NS]+vehicle, 2) rtPA+vehicle, 3) NS+MSCs, and 4) rtPA+MSCs. The incidence rate of intracerebral hemorrhage, both hemorrhagic and ischemic volume, and behavioral performance were examined. Matrix metalloproteinase–9 (MMP-9) levels in the brain were assessed with zymography. Quantitative analysis of regional cerebral blood flow (rCBF) was performed to assess hemodynamic change in the ischemic lesion.RESULTS: The MSC-treated groups (Groups 3 and 4) experienced a greater reduction in the incidence rate of intracerebral hemorrhage and hemorrhagic volume 1 day after tMCAO even if rtPA was received. The application of rtPA enhanced activation of MMP-9, but MSCs inhibited MMP-9 activation. Behavioral testing indicated that both MSC-infused groups had greater improvement than non-MSC groups had, but rtPA+MSCs provided greater improvement than MSCs alone. The rCBF ratio of rtPA groups (Groups 2 and 4) was similar at 2 hours after reperfusion of tMCAO, but both were greater than that in non-rtPA groups.CONCLUSIONS: Infused MSCs may inhibit endothelial dysfunction to suppress hemorrhagic events and facilitate functional outcome. Combined therapy of infused MSCs after rtPA therapy facilitated early behavioral recovery.