Human Mesenchymal Stem Cell-Derived Microvesicles Prevent the Rupture of Intracranial Aneurysm in Part by Suppression of Mast Cell Activation via a PGE2-Dependent Mechanism

Abstract

Background Activation of mast cells participates in the chronic inflammation associated with cerebral arteries in intracranial aneurysm formation and rupture. Several studies have shown that the anti-inflammatory effect of mesenchymal stem cells (MSCs) is beneficial for the treatment of aneurysms. However, some long-term safety concerns exist regarding stem cell-based therapy for clinical use. Objective We investigated the therapeutic potential of microvesicles (MVs) derived from human MSCs, anuclear membrane bound fragments with reparative properties, in preventing the rupture of intracranial aneurysm in mice, particularly in the effect of MVs on mast cell activation. Methods and Results Intracranial aneurysm was induced in C57BL/6 mice by the combination of systemic hypertension and intrathecal elastase injection. Intravenous administration of MSC-derived MVs on day 6 and day 9 after aneurysm induction significantly reduced the aneurysmal rupture rate, which was associated with reduced number of activated mast cells in the brain. A23187-induced activation of both primary cultures of murine mast cells and a human mast cell line, LAD2, was suppressed by MVs treatment, leading to a decrease in cytokine release and tryptase and chymase activities. Up-regulation of prostaglandin E2 (PGE2) production and E-prostanoid 4 (EP4) receptor expression were also observed on mast cells with MVs treatment. Administration of an EP4 antagonist with the MVs eliminated the protective effect of MVs against the aneurysmal rupture in vivo. Conclusions Human MSC-derived MVs prevented the rupture of intracranial aneurysm, in part due to their anti-inflammatory effect on mast cells, which was mediated by PGE2 production and EP4 activation.

Inflammation-Stimulated Mesenchymal Stromal Cell-Derived Extracellular Vesicles Attenuate Inflammation

“…Activin-A and Follistatin have been shown to modulate the inflammatory response (specifically TNF-a), leading to improved mortality [53]. Additionally, EVs have previously been shown to express COX2 and have varying lipid profiles [54,55], with some studies even indicating that PGE 2 may be involved in MSCEv activity [56]. Here, we found that EVs use COX2/PGE 2 to decrease TNF-a production in addition to other immunomodulatory mechanisms.…”

“…Additionally, EVs have previously been shown to express COX2 and have varying lipid profiles , with some studies even indicating that PGE 2 may be involved in MSCEv activity . Here, we found that EVs use COX2/PGE 2 to decrease TNF‐α production in addition to other immunomodulatory mechanisms.…”

SRPK1 gene silencing promotes vascular smooth muscle cell proliferation and vascular remodeling via inhibition of the PI3K/Akt signaling pathway in a rat model of intracranial aneurysms

“…IA results from the weakness of either the wall of cerebral vein or cerebral artery . The spontaneous rupturing of IAs contributes to a substantial amount of morbidity and mortality in patients with IA . Rupture of an IA is the most frequently occurring cause of subarachnoid hemorrhage, which is a lethal acute cerebrovascular disorder that commonly affects the working‐age population .…”

“…1 The spontaneous rupturing of IAs contributes to a substantial amount of morbidity and mortality in patients with IA. 2 Rupture of an IA is the most frequently occurring cause of subarachnoid hemorrhage, which is a lethal acute cerebrovascular disorder that commonly affects the working-age population. 3 A lifelong follow-up study pointed out that females are more prone to an aneurysm rupture, and Tobacco smoking is also an important factor that contributes to a higher possibility of rupture in patients with an unruptured IA (UIA) compared to UIA size factor.…”

Stem Cell Therapy in Heart Diseases – Cell Types, Mechanisms and Improvement Strategies

“…Beside the regulation of T cells and macrophages, MSCs were shown to suppress several other cells involved in the immune response including B cells [328,332,333], natural killer (NK) cells [334,335], dendritic cells [336][337][338] and mast cells [339][340][341]. Conflicting results were obtained for the interaction of MSCs and neutrophils.…”