title: 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: 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. 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. 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. Upregulation 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. 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. Stem Cells 2016;34:2943-2955.
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco, California, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco, California, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kuwabara
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco, California, USA.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Kamio
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco, California, USA.
authors.forename: Shuling
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco, California, USA.
authors.forename: Jeonghyun
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco, California, USA.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco, California, USA.
authors.forename: Jae-Woo
authors.initials: JW
authors.lastname: Lee
mesh_terms: D061605:Administration, Intravenous; D017542:Aneurysm, Ruptured / Q000473:pathology / Q000517:prevention & control* / Q000628:therapy; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D055252:Cell-Derived Microparticles / Q000187:drug effects / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects; D007165:Immunosuppression Therapy; D002532:Intracranial Aneurysm / Q000473:pathology / Q000517:prevention & control* / Q000628:therapy; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D012333:RNA, Messenger; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000001:Calcimycin; D015232:Dinoprostone
keywords: Intracranial aneurysm; Mast cells; Mesenchymal stem cells; Microvesicles; Prostaglandin E2