Matrix-dependent cardiac progenitor cell fate is instructed by the early regulation of YAP and Plk2

Although recent studies support regenerative potential based on cardiac progenitor cells (CPCs), it remains unclear what cues regulate CPC fate. Using 2- and 3D-culture models, we demonstrate that the two most abundantly expressed matrix proteins in the heart, laminin and fibronectin, have opposite roles in CPC fate decision. CPCs on fibronectin showed predominantly nuclear localization of the transcriptional co-activator YAP and maintained proliferation. In contrast, seeding on laminin induced cytosolic retention and degradation of YAP and altered gene expression, which preceded decreased proliferation and enhanced lineage commitment. RNA-sequencing identified Plk2 as candidate target gene of YAP. Plk2 expression depended on YAP stability, was rapidly downregulated on laminin, and its regulation was sufficient to rescue and/or mimic the CPC response to laminin and fibronectin, respectively. These findings propose a novel role of Plk2 and identify an early molecular mechanism in matrix-instructed CPC fate with potential implications for therapeutic cardiac regeneration.尽管近期研究证实基于心脏祖细胞（cardiac progenitor cells, CPCs）的再生潜能，但目前仍未明确究竟是何种信号调控CPC的细胞命运。本研究借助二维（2D）与三维（3D）培养模型，证实心脏中表达丰度最高的两种细胞外基质蛋白——层粘连蛋白（laminin）与纤连蛋白（fibronectin）——在CPC细胞命运抉择过程中发挥截然相反的调控作用。在纤连蛋白基质上培养的CPC，其转录共激活因子Yes相关蛋白（YAP）主要定位于细胞核，且维持增殖活性。与之相反，接种于层粘连蛋白基质的CPC会出现YAP的胞浆滞留与降解，同时伴随基因表达谱的改变；这一变化先于细胞增殖能力下降与谱系定向增强的进程。通过RNA测序（RNA-sequencing）技术，本研究鉴定出Polo样激酶2（Plk2）为YAP的候选靶基因。Plk2的表达依赖于YAP的蛋白稳定性，在层粘连蛋白基质上会被快速下调；且对Plk2的调控足以分别挽救CPC对层粘连蛋白的应答，或模拟其对纤连蛋白的应答反应。本研究结果揭示了Plk2的全新生物学功能，并阐明了基质调控CPC命运的早期分子机制，该发现或可为治疗性心脏再生研究带来潜在应用价值。