Khalafalla Farid G, Greene Steven, Khan Hashim, Ilves Kelli, Monsanto Megan M, Alvarez Roberto, Chavarria Monica, Nguyen Jonathan, Norman Benjamin, Dembitsky Walter P, Sussman Mark A
From the SDSU Heart Research Institute, San Diego State University, CA (F.G.K., S.G., H.K., K.I., M.M.M., R.A., M.C., J.N., B.N., M.A.S.); and Sharp Memorial Hospital, San Diego, CA (W.P.D.).
Circ Res. 2017 Nov 10;121(11):1224-1236. doi: 10.1161/CIRCRESAHA.117.310812. Epub 2017 Sep 18.
Autologous stem cell therapy using human c-Kit cardiac progenitor cells (hCPCs) is a promising therapeutic approach for treatment of heart failure (HF). However, hCPCs derived from aged patients with HF with genetic predispositions and comorbidities of chronic diseases exhibit poor proliferative and migratory capabilities, which impair overall reparative potential for injured myocardium. Therefore, empowering functionally compromised hCPCs with proregenerative molecules ex vivo is crucial for improving the therapeutic outcome in patients with HF.
To improve hCPC proliferation and migration responses that are critical for regeneration by targeting proregenerative P2Y nucleotide receptor (P2YR) activated by extracellular ATP and UTP molecules released following injury/stress.
c-Kit hCPCs were isolated from cardiac tissue of patients with HF undergoing left ventricular assist device implantation surgery. Correlations between P2 nucleotide receptor expression and hCPC growth kinetics revealed downregulation of select P2 receptors, including P2YR, in slow-growing hCPCs compared with fast growers. hCPC proliferation and migration significantly improved by overexpressing or stimulating P2YR. Mechanistically, P2YR-induced proliferation and migration were dependent on activation of YAP (yes-associated protein)-the downstream effector of Hippo signaling pathway.
Proliferation and migration of functionally impaired hCPCs are enhanced by P2YR-mediated YAP activation, revealing a novel link between extracellular nucleotides released during injury/stress and Hippo signaling-a central regulator of cardiac regeneration. Functional correlations exist between hCPC phenotypic properties and P2 purinergic receptor expression. Lack of P2YR and other crucial purinergic stress detectors could compromise hCPC responsiveness to presence of extracellular stress signals. These findings set the stage for subsequent studies to assess purinergic signaling modulation as a potential strategy to improve therapeutic outcome for use of hCPCs in patients with HF.
使用人c-Kit心脏祖细胞（hCPCs）进行自体干细胞治疗是治疗心力衰竭（HF）的一种有前景的治疗方法。然而，源自患有HF且有遗传易感性和慢性疾病合并症的老年患者的hCPCs表现出较差的增殖和迁移能力，这损害了受损心肌的整体修复潜力。因此，在体外使用促再生分子增强功能受损的hCPCs对于改善HF患者的治疗效果至关重要。
通过靶向由损伤/应激后释放的细胞外ATP和UTP分子激活的促再生P2Y核苷酸受体（P2YR），改善对再生至关重要的hCPC增殖和迁移反应。
从接受左心室辅助装置植入手术的HF患者的心脏组织中分离出c-Kit hCPCs。P2核苷酸受体表达与hCPC生长动力学之间的相关性显示，与快速生长的hCPCs相比，生长缓慢的hCPCs中包括P2YR在内的某些P2受体下调。通过过表达或刺激P2YR，hCPC的增殖和迁移显著改善。从机制上讲，P2YR诱导的增殖和迁移依赖于YAP（Yes相关蛋白）的激活——Hippo信号通路的下游效应器。
P2YR介导的YAP激活增强了功能受损的hCPCs的增殖和迁移，揭示了损伤/应激期间释放的细胞外核苷酸与Hippo信号（心脏再生的核心调节因子）之间的新联系。hCPC表型特性与P2嘌呤能受体表达之间存在功能相关性。缺乏P2YR和其他关键的嘌呤能应激探测器可能会损害hCPC对细胞外应激信号存在的反应性。这些发现为后续研究评估嘌呤能信号调节作为一种潜在策略以改善HF患者使用hCPCs的治疗效果奠定了基础。
