Abstract
Transplantation of mesenchymal stem cells (MSCs) was reported to improve functional outcomes in a rat model of ischemic stroke, and subsequent studies suggest that MSC-derived microvesicles (MVs) can replace the beneficial effects of MSCs. Here, we evaluated three different MSC-derived MVs, including MVs from untreated MSCs (MSC-MVs), MVs from MSCs treated with normal rat brain extract (NBE-MSC-MVs), and MVs from MSCs treated with stroke-injured rat brain extract (SBE-MSC-MVs), and tested their effects on ischemic brain injury induced by permanent middle cerebral artery occlusion (pMCAO) in rats. NBE-MSC-MVs and SBE-MSC-MVs had significantly greater efficacy than MSC-MVs for ameliorating ischemic brain injury with improved functional recovery. We found similar profiles of key signalling proteins in NBE-MSC-MVs and SBE-MSC-MVs, which account for their similar therapeutic efficacies. Immunohistochemical analyses suggest that brain-extract—treated MSC-MVs reduce inflammation, enhance angiogenesis, and increase endogenous neurogenesis in the rat brain. We performed mass spectrometry proteomic analyses and found that the total proteomes of brain-extract—treated MSC-MVs are highly enriched for known vesicular proteins. Notably, MSC-MV proteins upregulated by brain extracts tend to be modular for tissue repair pathways. We suggest that MSC-MV proteins stimulated by the brain microenvironment are paracrine effectors that enhance MSC therapy for stroke injury.
Highlights
Cell transplantation may become a therapeutic option for patients with central nervous system (CNS) diseases
We investigated whether mesenchymal stem cells (MSCs)-MVs and MVs isolated from MSCs treated with normal (NBE-MSC-MVs) and stroke (SBE-MSC-MVs) rat brain extract would improve functional recovery and tissue regeneration after the administration into a rat model of stroke induced by permanent middle cerebral artery occlusion
We hypothesised that MVs from MSCs significantly contribute to the observed benefits of MSC administration, and signalling molecules secreted from a damaged microenvironment could enhance the therapeutic effect of MSC-MVs
Summary
Cell transplantation may become a therapeutic option for patients with central nervous system (CNS) diseases. The rare event of cellular transdifferentiation of MSCs into neural cells, followed by integration into complex neural connections, may take weeks or months[6,7]. These results suggest that paracrine factors from MSCs could provide a promising treatment strategy for various CNS diseases. We hypothesised that culturing MSCs with brain extract in vitro would elicit cell responses and changes in the composition of their secretomes, including changes in soluble factors and MVs known to regulate cell proliferation, differentiation, inflammation, tissue regeneration, and angiogenesis. We investigated whether MSC-MVs and MVs isolated from MSCs treated with normal (NBE-MSC-MVs) and stroke (SBE-MSC-MVs) rat brain extract would improve functional recovery and tissue regeneration after the administration into a rat model of stroke induced by permanent middle cerebral artery occlusion (pMCAO)
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