Wnt信号共受体LRP6调控心肌再生的作用和机制

The mammal adult heart was traditionally viewed as a terminally differentiated organ, which virtually has no capacity for regeneration following cardiac injury. Low-density lipoprotein receptor-related protein-6 (LRP6) serves as a Wnt signaling coreceptor to control the cardiac development; however, its role in the adult cardiac pathophysiology remains unclear. There has been a consistent viewpoint that LRP6 has little function in adult heart. Unexpectedly, we found that Lrp6 deletion in cardiomyocytes significantly promoted neonatal myocyte proliferation, extended the postnatal proliferative window of cardiomyocytes, and for re-activation of cardiomyocyte mitosis in the adult heart. LRP6 reduction does not affect the expression and nucleocytoplasmic distribution of β-catenin protein. We speculate that LRP6 is a critical regulator of the cardiomyocyte cell cycle, LRP6 deletion promotes regenerative repairment after myocardial injury. On the basis of these preliminary findings, the proposal aims to determine the function of LRP6 on postnatal cardiomyocyte cell cycle arrest, and further to decipher the mechanism details and signaling pathway. Finally, we will show the roles of LRP6 in myocardial damage repair using a series of model animals and disease model. The project will reveal a novel property of LRP6 beyond the Wnt coreceptor and elucidate a novel biological function of LRP6 in cardiac regeneration, which will provide a new avenue for the intervention of myocardial damage repair and heart failure.

传统观点认为，成体哺乳动物心脏为终末分化器官，在心肌损伤时不具备再生能力。Wnt信号共受体LRP6介导经典的Wnt/β-catenin信号，调控心脏发育；然而，其在成体心脏中的功能并不清楚。我们意外地发现，LRP6缺失显著地促进新生鼠心肌细胞增殖，延长心肌细胞可增殖时间窗；特别重要的是，它的失活还使得成体心肌细胞重新进行有丝分裂；LRP6缺失并不影响心肌细胞β-catenin的表达和核浆分布。我们推测：LRP6是心肌细胞周期的关键调控因子，LRP6缺失促进心肌损伤后的再生修复。本项目拟在上述前期工作基础上，首先证明LRP6缺失具备解除心肌细胞周期阻滞的生物学功能，进而探索LRP6调控心肌再生的细胞机制和信号通路，最终借助系列模式动物和疾病模型揭示其在心肌损伤修复中的作用。该研究将有望确立LRP6独立于Wnt信号的全新细胞生物学作用，从新的视角为未来心肌损伤修复和心力衰竭的干预提供新的理念。

哺乳动物的心肌细胞在出生后迅速退出细胞周期，失去增殖能力。成体心肌细胞几乎不能自我更新，以致心脏难以应对多种病理因素带来的心肌损伤。激活心肌细胞有丝分裂信号通路，使已经存在的成体心肌细胞去分化重新进入细胞周期，增加有功能的心肌细胞数量，成为心肌损伤修复的干预策略之一。在本项目的资助下，我们聚焦于低密度脂蛋白受体相关蛋白6（LRP6）在心肌细胞增殖与心肌梗死损伤修复中的作用。采用细胞生物学、分子生物学、生物信息学及模式生物学等方面的技术，从整体、器官、组织和细胞水平探索了LRP6调控心肌再生的分子机制。我们发现LRP6下调可以促进心肌细胞增殖，延长心肌细胞的可增殖时间窗。LRP6缺失通过促进心肌细胞增殖降低小鼠的心肌梗死面积比例，从而改善心脏功能。机制研究发现，Ing5/P21通路介导了LRP6对心肌细胞增殖的调控。该研究揭示了LRP6在成体心脏心肌再生中的作用及其调控机制，将为心肌损伤修复的干预策略研究提供一个新的靶点。本项目合计发表标注受项目资助的SCI论文12篇，代表性研究成果发表在《Cell Research》等领域内权威刊物上。