Rejuvenation of human cardiac progenitor cells with Pim-1 kinase.
Rejuvenation of human cardiac progenitor cells with Pim-1 kinase.
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DOI：
10.1161/circresaha.113.302302
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发表时间：
2013-10-25
影响因子：
20.1
通讯作者：
Sussman MA
中科院分区：
文献类型：
--
作者：
Mohsin S;Khan M;Nguyen J;Alkatib M;Siddiqi S;Hariharan N;Wallach K;Monsanto M;Gude N;Dembitsky W;Sussman MA
通过将人心脏祖细胞 (hCPC) 过继转移到患有病理学问题的心脏中，可以增强心肌功能。然而，心力衰竭患者的高龄、合并症和心肌损伤限制了 hCPC 的增殖、存活和再生能力。衰老 hCPC 的复兴将改善大量拥有功能受损干细胞的患者群体的再生治疗结果。通过 Pim-1 离体修饰逆转 hCPC 的表型和功能衰老。从接受左心室辅助装置植入的患者的心脏活检样本中分离出 C-kit 阳性 hCPC。从多个患者分离的 hCPC 之间的生长动力学、端粒长度和细胞周期调节因子的表达显示出显着差异。与具有快速生长动力学的 hCPC 相比，具有缓慢生长动力学的 hCPC 中的端粒长度显着缩短，同时伴有增殖减少和衰老标记物上调。通过使用 Pim-1 激酶进行基因修饰，hCPC 被赋予了理想的年轻特征，包括增殖、端粒长度、存活率的增加和衰老标志物表达的减少。 Pim-1 激酶可改善 hCPC 的衰老特征，从而使表型和功能特性恢复活力。 hCPC 显示出因 Pim-1 修饰而改善的细胞特性，但相对于具有快速生长动力学的 hCPC，具有缓慢生长动力学的 hCPC 的益处更为明显。由于大多数心力衰竭患者年龄较大、虚弱且再生能力受损，因此应将 Pim-1 修饰的使用纳入基于细胞的治疗方法中，以扩大纳入标准并解决与老年 hCPC 衰老表型相关的局限性。
Myocardial function is enhanced by adoptive transfer of human cardiac progenitor cells (hCPCs) into a pathologically challenged heart. However, advanced age, comorbidities, and myocardial injury in patients with heart failure constrain the proliferation, survival, and regenerative capacity of hCPCs. Rejuvenation of senescent hCPCs will improve the outcome of regenerative therapy for a substantial patient population possessing functionally impaired stem cells. Reverse phenotypic and functional senescence of hCPCs by ex vivo modification with Pim-1. C-kit–positive hCPCs were isolated from heart biopsy samples of patients undergoing left ventricular assist device implantation. Growth kinetics, telomere lengths, and expression of cell cycle regulators showed significant variation between hCPC isolated from multiple patients. Telomere length was significantly decreased in hCPC with slow-growth kinetics concomitant with decreased proliferation and upregulation of senescent markers compared with hCPC with fast-growth kinetics. Desirable youthful characteristics were conferred on hCPCs by genetic modification using Pim-1 kinase, including increases in proliferation, telomere length, survival, and decreased expression of senescence markers. Senescence characteristics of hCPCs are ameliorated by Pim-1 kinase resulting in rejuvenation of phenotypic and functional properties. hCPCs show improved cellular properties resulting from Pim-1 modification, but benefits were more pronounced in hCPC with slow-growth kinetics relative to hCPC with fast-growth kinetics. With the majority of patients with heart failure presenting advanced age, infirmity, and impaired regenerative capacity, the use of Pim-1 modification should be incorporated into cell-based therapeutic approaches to broaden inclusion criteria and address limitations associated with the senescent phenotype of aged hCPC.