Microvesicles from brain-extract—treated mesenchymal stem cells improve neurological functions in a rat model of ischemic stroke

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.

Stem cell therapy for abrogating stroke-induced neuroinflammation and relevant secondary cell death mechanisms

“…Bone marrow-derived mesenchymal stem cells (BM-MSCs) are a multipotent sub-class of MSCs, harvested from bone marrow, which exhibit the capacity to differentiate into mesenchymal tissues, including osteogenic, chondrogenic, and adipogenic cells (Wang et al, 2016). Transplantation of BM-MSCs has been shown to encourage improvements in neurologic function following cerebral ischemia in stroke models (Lee et al, 2016). BM-MSCs may promote functional improvements in part due to the secretion of neurotrophic factors, which in turn stimulate endogenous cerebral repair processes.…”

“…It remains to be determined if BM-MSCs differentiate into functional neurons, especially in light of their low survival time after transplantation, but their influence on neurogenesis is clear. In addition to secretion of the neurotrophic factors listed above, BM-MSCs may also improve rates of angiogenesis, thereby helping to encourage perfusion at the site of injury (Lee et al, 2016; Li et al, 2016). …”

The Role of Astrocytes in Neuroprotection after Brain Stroke: Potential in Cell Therapy

“…Transplantation models have been reported in cerebral ischemia mainly using mesenchymal stem cells (MSC; Hsuan et al, 2016; Lee et al, 2016), induced pluripotent stem cells (iPSCs; Mohamad et al, 2013), and NSCs (Huang et al, 2014; Gervois et al, 2016), showing that there is stimulus of endogenous activity of cells in the injured tissue, generating increased angiogenesis/neovascularization and release of trophic factors, which is chiefly secreted by these cells, allowing the migration to the lesion zone. Likewise, there is axonal recovery, dendritic branching, and synaptogenesis, which are reported mainly surrounding the injury site (Horie et al, 2015).…”

Brain-Derived Extracellular Vesicles are Highly Enriched in the Prion Protein and Its C1 Fragment: Relevance for Cellular Uptake and Implications in Stroke

“…In the case of brain disorders, they are very attractive because of their property to cross the BBB when genetically modified to target the brain 64 . A protective role of EVs derived from mesenchymal cells in a variety of brain insults and disorders 65 , including stroke [66][67][68][69] , has also been shown. Until recently, most of the EVs assessed in various studies were isolated from cell culture supernatants or body fluids, but the isolation of EVs from complex tissue such as the brain parenchyma has been increasingly reported only in the last few years 42, 70,71 .…”