Cardiosphere-derived cells from pediatric end-stage heart failure patients have enhanced functional activity due to the heat shock response regulating the secretome.
Cardiosphere-derived cells from pediatric end-stage heart failure patients have enhanced functional activity due to the heat shock response regulating the secretome.
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DOI：
10.1002/stem.1937
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发表时间：
2015-04
期刊：
影响因子：
--
通讯作者：
Kaushal S
中科院分区：
文献类型：
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作者：
Sharma S;Mishra R;Simpson D;Wehman B;Colletti EJ;Deshmukh S;Datla SR;Balachandran K;Guo Y;Chen L;Siddiqui OT;Kaushal S;Kaushal S
我们已经证明，来自年轻人的人类新生儿心脏球源细胞(CDCs)由于其强大的分泌体而具有更强的再生能力。然而，目前尚不清楚失代偿的儿童心脏如何影响其CDC的功能活动。我们的目的是鉴定来自正常功能的心脏病(CHD)患者和来自年龄匹配的终末期心力衰竭(ESHF)患者的DC的效力，并确定其中的机制。ESHF来源的CDCs含有较多的c-kit+、Islet-1+和Sca-1+细胞。与CHD患者相比，将ESHF来源的CDCs移植到梗塞的啮齿动物模型中，显著地显示出更高的心功能恢复，防止不利的重构，并增强血管生成。ESHF来源的CDCs功能的恢复部分是通过增加sdf-1α和血管内皮生长因子A的分泌，增加内源性干细胞的募集和心肌细胞的增殖来实现的。我们确定其机制是由于热休克反应(HSR)引导的分泌组，这一点得到了三条证据的支持。首先，功能增益研究表明，HSR的增加导致低功能的CHD来源的CDC显著恢复心肌功能。其次，针对HSR的功能丧失研究削弱了ESHF来源的CDCs功能恢复受损心肌的能力。最后，天然ESHF心肌中c-kit+CSCs的数量增加。这些结果表明，高铁蛋白通过增加其分泌体活性，尤其是SDF-1α和血管内皮生长因子-A，来增强ESHF来源的CDC的功能活性。
We have demonstrated that human neonatal cardiosphere derived cells (CDCs) derived from the young are more regenerative due to their robust secretome. However, it is unclear how the decompensated pediatric heart impacts the functional activity of their CDCs. Our aim was to characterize the potency of pediatric CDCs derived from normal functioning myocardium of control heart disease (CHD) patients to those generated from age matched end stage heart failure (ESHF) patients and determine the mechanisms involved. ESHF derived CDCs contained a higher number of c-kit+, Islet-1+, and Sca-1+ cells. When transplanted into an infarcted rodent model, ESHF derived CDCs significantly demonstrated higher restoration of ventricular function, prevented adverse remodeling, and enhanced angiogenesis when compared to CHD patients. The superior functional recovery of the ESHF derived CDCs was mediated in part by increased SDF-1α and VEGF-A secretion resulting in augmented recruitment of endogenous stem cells and proliferation of cardiomyocytes. We determined the mechanism is due to the secretome directed by the heat shock response (HSR), which is supported by three lines of evidence. Firstly, gain of function studies demonstrated that increased HSR induced the lower functioning CHD derived CDCs to significantly restore myocardial function. Secondly, loss-of function studies targeting the HSR impaired the ability of the ESHF derived CDCs to functionally recover the injured myocardium. Finally, the native ESHF myocardium had an increased number of c-kit+ CSCs. These findings suggest that the HSR enhances the functional activity of ESHF derived CDCs by increasing their secretome activity, notably SDF-1α and VEGF-A.