Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement
Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement
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DOI：
10.1096/fj.05-5211com
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发表时间：
2006-04-01
期刊：
影响因子：
4.8
通讯作者：
Dzau, Victor J.
中科院分区：
文献类型：
--
作者：
Gnecchi, Massimiliano;He, Huamei;Dzau, Victor J.
我们先前曾报道，心肌内注射过表达Akt的骨髓间充质干细胞（Akt - MSCs）可抑制心肌梗死后2周所测的心室重构并恢复心脏功能。在此，我们报道这种功能改善在（心肌梗死后）72小时就已出现。这种早期显著的效应不能轻易归因于供体细胞的心肌再生。因此，我们假设细胞通过释放可溶性因子所发挥的旁分泌作用可能是注射Akt - MSCs后组织修复和功能改善的重要机制。事实上，在当前研究中我们证明，缺氧的Akt - MSCs的条件培养基在体外显著抑制缺氧诱导的细胞凋亡，并引发成年大鼠心肌细胞强烈的自发性收缩。当注入梗死心脏时，Akt - MSC条件培养基相对于对照组显著限制梗死面积并改善心室功能。支持旁分泌假说的数据显示，编码一些因子（血管内皮生长因子、成纤维细胞生长因子 - 2、肝细胞生长因子、胰岛素样生长因子 - I和胸腺素β4）的若干基因在Akt - MSCs中显著上调，特别是在缺氧条件下，这些因子是Akt - MSC条件培养基所发挥作用的潜在介质。综上所述，我们的数据支持Akt - MSC介导的心肌保护和功能改善的旁分泌机制。——格内基（Gnecchi），M.；何（He），H.；努瓦索（Noiseux），N.；梁（Liang），O.D.；张（Zhang），L.；莫雷洛（Morello），F.；穆（Mu），H.；梅洛（Melo），L.G.；普拉特（Pratt），R.E.；英格沃尔（Ingwall），J.S.；卓（Dzau），V.J. 支持Akt修饰的间充质干细胞介导的心脏保护和功能改善的旁分泌假说的证据
We previously reported that intramyocardial injection of bone marrow-derived mesenchymal stem cells overexpressing Akt (Akt-MSCs) inhibits ventricular remodeling and restores cardiac function measured 2 wk after myocardial infarction. Here, we report that the functional improvement occurs in (c) 72 h. This early remarkable effect cannot be readily attributed to myocardial regeneration from the donor cells. Thus, we hypothesized that paracrine actions exerted by the cells through the release of soluble factors might be important mechanisms of tissue repair and functional improvement after injection of the Akt-MSCs. Indeed, in the current study we demonstrate that conditioned medium from hypoxic Akt-MSCs markedly inhibits hypoxia-induced apoptosis and triggers vigorous spontaneous contraction of adult rat cardiomyocytes in vitro. When injected into infarcted hearts, the Akt-MSC conditioned medium significantly limits infarct size and improves ventricular function relative to controls. Support to the paracrine hypothesis is provided by data showing that several genes, coding for factors ( VEGF, FGF-2, HGF, IGF-I, and TB4) that are potential mediators of the effects exerted by the Akt-MSC conditioned medium, are significantly up-regulated in the Akt-MSCs, particularly in response to hypoxia. Taken together, our data support Akt-MSC-mediated paracrine mechanisms of myocardial protection and functional improvement. -Gnecchi, M., He, H., Noiseux, N., Liang, O. D., Zhang, L., Morello, F., Mu, H., Melo, L. G., Pratt, R. E., Ingwall, J. S., Dzau, V. J. Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement.