Mesenchymal Stem Cells Overexpressing Interleukin-10 Promote Neuroprotection in Experimental Acute Ischemic Stroke

Abstract

Interleukin (IL)-10 is a contributing factor to neuroprotection of mesenchymal stem cell (MSC) transplantation after ischemic stroke. Our aim was to increase therapeutic effects by combining MSCs and ex vivo IL-10 gene transfer with an adeno-associated virus (AAV) vector using a rat transient middle cerebral artery occlusion (MCAO) model. Sprague-Dawley rats underwent 90 min MCAO followed by intravenous administration of MSCs alone or IL-10 gene-transferred MSCs (MSC/IL-10) at 0 or 3 hr after ischemia reperfusion. Infarct lesions, neurological deficits, and immunological analyses were performed within 7 days after MCAO. 0-hr transplantation of MSCs alone and MSC/IL-10 significantly reduced infarct volumes and improved motor function. Conversely, 3-hr transplantation of MSC/IL-10, but not MSCs alone, significantly reduced infarct volumes (p < 0.01) and improved motor function (p < 0.01) compared with vehicle groups at 72 hr and 7 days after MCAO. Immunological analysis showed that MSC/IL-10 transplantation significantly inhibits microglial activation and pro-inflammatory cytokine expression compared with MSCs alone. Moreover, overexpressing IL-10 suppressed neuronal degeneration and improved survival of engrafted MSCs in the ischemic hemisphere. These results suggest that overexpressing IL-10 enhances the neuroprotective effects of MSC transplantation by anti-inflammatory modulation and thereby supports neuronal survival during the acute ischemic phase.

Microglial polarization in posttraumatic epilepsy: Potential mechanism and treatment opportunity

“…Similar beneficial effects of IL‐10 administration have been reported after fluid‐percussion TBI . IL‐10 expressing MSCs can also induce M2 polarization in other brain pathologies that have epileptogenic potential such as stroke and improve functional outcomes …”

“…77 IL-10 expressing MSCs can also induce M2 polarization in other brain pathologies that have epileptogenic potential such as stroke and improve functional outcomes. 78 IL-4 and IL-13 are other immunoregulatory cytokines that have great potential in triggering M2 polarization by acting on their common heterodimeric receptor composed of the IL-13 receptor α1 (IL-13Rα1) and IL-4Rα subunits. 79 This in turn activates downstream signaling cascades including the JAK/STAT6, insulin receptor substrate, and phosphatidylinositol 3′-kinase pathways, leading to the transcription of genes relevant to M2like microglia polarization.…”

Rat Olfactory Mucosa Mesenchymal Stem/Stromal Cells (OM-MSCs): A Characterization Study

“…Unexpected is the relatively high concentrations of IL-2 in the CM of OM-MSCs. MSCs can control the production and secretion of IL-2 and T cells IL-2 response through the secretion of IL-10 [131,132]. It is possible that the hostile environment triggered by the conditioning of OM-MSCs over 48 h may be enough to induce a proinflammatory response and production of IL-2, which would also explain the production and secretion, although to a lesser extent, of other biomarkers such as TNF-α, IFN-γ and IL-18.…”

Treating childhood traumatic brain injury with autologous stem cell therapy

“…Many factors contribute to the success of stem cell transplantation, including timing, route, and cell dosage. In terms of the timing of the stem cell therapy, injection upon injury (acutely) tends to lessen inflammation and cell death while injection at a later time (chronically) improves long-term function [35, 38–39]. Specifically, acute injuries tend to weaken the blood brain barrier (BBB), providing a narrow therapeutic window for injection of stem cells directly into the central nervous system (CNS) [35].…”

“…Because cell engraftment is not necessarily needed for neuroprotection, less invasive methods or even stem cell-free products will likely be sufficient in improving patient outcomes [48]. Accumulating evidence suggests that beneficial effects associated with stem cell therapy may come from factors or cell components released by the cells upon injection, such as exosomes and microvesicles, altogether advancing the concept of stem cell-free products as alternative sources for transplantation [39]. The advent of such stem cell-free products may allow reduction for the needed cell dose to achieve clinically effective outcomes.…”