Mesenchymal Stem Cells and Cardiomyocytes Interplay to Prevent Myocardial Hypertrophy
Mesenchymal Stem Cells and Cardiomyocytes Interplay to Prevent Myocardial Hypertrophy
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间充质干细胞和心肌细胞相互作用以预防心肌肥厚。
DOI：
10.5966/sctm.2015-0032
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发表时间：
2015-12-01
影响因子：
6
通讯作者：
Lu, Yanjie
中科院分区：
文献类型：
--
作者：
Cai, Benzhi;Tan, Xueying;Lu, Yanjie
骨髓间充质干细胞（BMSCs）已成为心血管疾病的一种有前途的治疗策略。然而，目前尚无证据表明骨髓间充质干细胞可以修复病理性心肌肥厚。本研究将骨髓间充质干细胞与新生大鼠心室肌细胞（NRVC）体外间接共培养或心肌内移植到肥大的心脏中。结果表明，BMSCs在体外共培养模型和体内移植后均能阻止异丙肾上腺素（ISO）诱导的心肌细胞典型肥大特征。此外，在体外和体内BMSCs的存在下，NRVC中的激活的T细胞胞质3（NFATc 3）肥大通路的Ca 2 +/钙调神经磷酸酶/核因子的激活被废除。有趣的是，抑制血管内皮生长因子（VEGF）从BMSCs释放，而不是碱性成纤维细胞生长因子和胰岛素样生长因子1，取消了BMSCs对心肌细胞肥大的保护作用。因此，VEGF给药减弱了ISO诱导的细胞体积增大;心房利钠肽、脑利钠肽和fl-肌球蛋白重链表达上调;以及Ca 2 +/钙调神经磷酸酶/NFATc 3肥大通路的激活，这些通路可以通过阻断心肌细胞中的VEGFR-1而被废除，表明VEGF受体1参与了VEGF的抗肥大作用。我们进一步发现，丰富的VEGF分泌有助于BMSCs的抗肥大作用来源于BMSCs和心肌细胞的串扰，而不是单独的BMSCs或心肌细胞。间充质干细胞与心肌细胞的相互作用对VEGF的释放产生协同作用。总之，间充质干细胞和心肌细胞之间的串扰有助于通过抑制心肌细胞中的Ca 2 +/钙调神经磷酸酶/NFATc 3肥大途径来抑制心肌肥大。这些结果为骨髓间充质干细胞治疗心肌肥大提供了第一个证据。
Bone marrow-derived mesenchymal stem cells (BMSCs) have emerged as a promising therapeutic strategy for cardiovascular disease. However, there is no evidence so far that BMSCs can heal pathological myocardial hypertrophy. In this study, BMSCs were indirectly cocultured with neonatal rat ventricular cardiomyocytes (NRVCs) in vitro or intramyocardially transplanted into hypertrophic hearts in vivo. The results showed that isoproterenol (ISO)-induced typical hypertrophic characteristics of cardiomyocytes were prevented by BMSCs in the coculture model in vitro and after BMSC transplantation in vivo. Furthermore, activation of the Ca2+/calcineurin/nuclear factor of activated T cells cytoplasmic 3 (NFATc3) hypertrophic pathway in NRVCs was abrogated in the presence of BMSCs both in vitro and in vivo. Interestingly, inhibition of vascular endothelial growth factor (VEGF) release from BMSCs, but not basic fibroblast growth factor and insulin-like growth factor 1, abolished the protective effects of BMSCs on cardiomyocyte hypertrophy. Consistently, VEGF administration attenuated ISO-induced enlargement of cellular size; the upregulation of atrial natriuretic peptide, brain natriuretic peptide, and fl-myosin heavy chain expression; and the activation of Ca2+/calcineurin/NFATc3 hypertrophic pathways, and these pathways can be abrogated by blocking VEGFR-1 in cardiomyocytes, indicating that VEGF receptor 1 is involved in the antihypertrophic role of VEGF. We further found that the ample VEGF secretion contributing to the antihypertrophic effects of BMSCs originates from the crosstalk of BMSCs and cardiac cells but not BMSCs or cardiomyocytes alone. Interplay of mesenchymal stem cells with cardiomyocytes produced synergistic effects on VEGF release. In summary, crosstalk between mesenchymal stem cells and cardiomyocytes contributes to the inhibition of myocardial hypertrophy via inhibiting Ca2+/calcineurin/NFATc3 hypertrophic pathways in cardiac cells. These results provide the first evidence for the treatment of myocardial hypertrophy using BMSCs.