Sharma Sudhish, Mishra Rachana, Simpson David, Wehman Brody, Colletti Evan J, Deshmukh Savitha, Datla Srinivasa Raju, Balachandran Keerti, Guo Yin, Chen Ling, Siddiqui Osama T, Kaushal Shalesh, Kaushal Sunjay
Division of Cardiac Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Stem Cells. 2015 Apr;33(4):1213-29. doi: 10.1002/stem.1937.
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 to 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 with 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. First, gain of function studies demonstrated that increased HSR induced the lower functioning CHD-derived CDCs to significantly restore myocardial function. Second, 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(+) cardiac stem cells. 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.
我们已经证明，源自年轻人的人类新生儿心脏球衍生细胞（CDC）因其强大的分泌组而具有更强的再生能力。然而，失代偿的小儿心脏如何影响其CDC的功能活性尚不清楚。我们的目的是表征源自对照心脏病（CHD）患者正常功能心肌的小儿CDC与年龄匹配的终末期心力衰竭（ESHF）患者产生的CDC的效力，并确定其中涉及的机制。源自ESHF的CDC含有更多数量的c-kit(+)、Islet-1(+)和Sca-1(+)细胞。当移植到梗死的啮齿动物模型中时，与CHD患者相比，源自ESHF的CDC显著显示出更高的心室功能恢复、预防不良重塑并增强血管生成。源自ESHF的CDC的卓越功能恢复部分是由SDF-1α和VEGF-A分泌增加介导的，导致内源性干细胞募集增加和心肌细胞增殖。我们确定其机制是由于热休克反应（HSR）指导的分泌组，这得到了三条证据的支持。首先，功能获得研究表明，HSR增加可诱导功能较低的源自CHD的CDC显著恢复心肌功能。其次，针对HSR的功能丧失研究损害了源自ESHF的CDC功能恢复受损心肌的能力。最后，天然ESHF心肌中c-kit(+)心脏干细胞数量增加。这些发现表明，HSR通过增加其分泌组活性，特别是SDF-1α和VEGF-A，增强了源自ESHF的CDC的功能活性。
