骨髓间充质干细胞通过调节单核∕巨噬细胞亚型分化抑制小鼠主动脉瘤形成和扩张的机制研究

Aortic aneurysm (AA) is a common condition that is associated with a risk of rupture and sudden death. Despite current improvements in therapeutic options, including open surgical and endovascular aneurysm repairs, nonsurgical prevention of AA growth and rupture has yet to be achieved. Monocytes/ macrophages are key effector cells that destabilize the extracellular matrix in the arterial wall and play a pivotal role in the pathogenesis of AA. Bone marrow-derived mesenchymal stem cells (BM-MSCs) have been proposed to attenuate AA formation and progression, but their mechanism of action is complex and not fully understood. In our previous study, BM-MSCs decreased infiltration of M1 macrophages in aortic medial layers, however increased percentage of M2 macrophages in the adventitia，which suggested switch phenotype of monocytes/macrophages is involved in the protective role of MSCs in AA. However, the interactions between BM-MSCs and monocytes/ macrophages in the repair progress of AA, especially whether BM-MSCs can induce the polarization of macrophages in aortic tissues, are poorly understood. In the present study, we wish to test the hypothesis that BM-MSCs mediate a switch in the circulating and infiltrating monocyte/macrophage phenotype in AA, thereby influencing the formation and progression of AA, which may provide a novel explanation for the mechanism underlying the aortic protective role of BM-MSCs.

主动脉瘤是一种严重危害人类健康的慢性退行性血管疾病。对于主动脉瘤直径较小、无症状的患者和无法耐受手术的高危患者，目前缺乏有效的治疗方法。单核/巨噬细胞在主动脉瘤发生和发展中发挥至关重要的作用。骨髓间充质干细胞（BM-MSCs）具有良好的免疫调节和抗炎症作用。申请人和其他学者相继报道，BM-MSCs通过抗炎症反应抑制主动脉瘤的形成和扩张,然而其确切机制尚未阐明。在前期实验中， BM-MSCs移植减少主动脉瘤组织M1型巨噬细胞浸润同时，还增加抗炎症反应的M2型巨噬细胞比例，说明巨噬细胞亚型分化在BM-MSCs治疗主动脉瘤过程中发挥重要作用。本研究在前期研究基础之上，通过一系列体内和体外实验探讨BM-MSCs对单核/巨噬细胞的免疫调节作用，以及单/巨噬细胞在BM-MSCs抑制主动脉瘤发生和扩张过程中所起的作用，从而揭示BM-MSCs治疗主动脉瘤的作用机制，为BM-MSCs的临床应用提供必要的理论基础和依据。

主动脉瘤(AA)是一种具有显著自身免疫性疾特征,严重危害人类健康的慢性退行性血管疾病。对于主动脉瘤直径较小、无症状的患者和无法耐受手术的高危患者，目前缺乏有效的治疗方法。单核/巨噬细胞在主动脉瘤发生和发展中发挥至关重要的作用。骨髓间充质干细胞（BM-MSCs）具有良好的免疫调节和抗炎症作用。BM-MSCs通过抗炎症反应抑制主动脉瘤的形成和扩张,然而其确切机制尚未阐明。我们研究发现，BM-MSCs移植减少主动脉瘤组织M1型巨噬细胞浸润同时，还增加抗炎症反应的M2型巨噬细胞比例，说明巨噬细胞亚型分化在BM-MSCs治疗主动脉瘤过程中发挥重要作用。本研究通过一系列体内和体外实验进一步探讨BM-MSCs对单核/巨噬细胞的免疫调节作用，以及单核/巨噬细胞亚型分化在BM-MSCs抑制主动脉瘤发生和扩张过程中所起的作用，证实BM-MSCs通过调节单核/巨噬细胞亚型分化从而达到抗炎症反应抑制主动脉瘤的扩展。