Rationale: 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.

Objective: To improve hCPC proliferation and migration responses that are critical for regeneration by targeting proregenerative P2Y₂ nucleotide receptor (P2Y₂R) activated by extracellular ATP and UTP molecules released following injury/stress.

Methods and Results: 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 P2Y₂R, in slow-growing hCPCs compared with fast growers. hCPC proliferation and migration significantly improved by overexpressing or stimulating P2Y₂R. Mechanistically, P2Y₂R-induced proliferation and migration were dependent on activation of YAP (yes-associated protein)—the downstream effector of Hippo signaling pathway.

Conclusions: Proliferation and migration of functionally impaired hCPCs are enhanced by P2Y₂R-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 P2Y₂R 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.

中文翻译：

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P2Y ₂核苷酸受体通过调节河马信号的新颖性和意义来促进人类心脏祖细胞的活化。

基本原理：使用人c-Kit ⁺心脏祖细胞（hCPC）的自体干细胞疗法是一种有前途的心力衰竭（HF）治疗方法。然而，源自具有遗传易感性和慢性病合并症的老年HF患者的hCPC显示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，离体使用前体再生分子赋予功能受损的hCPCs对改善HF患者的治疗效果至关重要。

目的：通过损伤/应激后释放的细胞外ATP和UTP分子激活的前再生P2Y ₂核苷酸受体（P2Y ₂ R），改善对于再生至关重要的hCPC增殖和迁移反应。

方法和结果：从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 ⁺ hCPC。P2核苷酸受体表达与hCPC生长动力学之间的关系表明，与快速生长的hCPC相比，生长缓慢的hCPC中P2Y ₂ R（包括P2Y ₂ R）的选择P2受体的表达下调。hCPC的增殖和迁移可通过过度表达或刺激P2Y ₂ R而得到显着改善。从机械上讲，P2Y ₂ R诱导的增殖和迁移取决于YAP（是相关蛋白）的激活，YAP是河马信号通路的下游效应子。

结论： P2Y ₂ R介导的YAP活化增强了功能受损的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信号传导之间的新型联系，Hippo信号传导是心脏再生的中央调节器。hCPC表型属性和P2嘌呤能受体表达之间存在功能相关性。缺乏P2Y ₂ R和其他重要的嘌呤能应激检测器可能会损害hCPC对细胞外应激信号的反应。这些发现为后续研究评估嘌呤能信号转导奠定了基础，嘌呤能信号转导调节是改善在HF患者中使用hCPC的治疗结果的潜在策略。