National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Protein Cell. 2023 Apr 21;14(4):279-293. doi: 10.1093/procel/pwac038.
Aging poses a major risk factor for cardiovascular diseases, the leading cause of death in the aged population. However, the cell type-specific changes underlying cardiac aging are far from being clear. Here, we performed single-nucleus RNA-sequencing analysis of left ventricles from young and aged cynomolgus monkeys to define cell composition changes and transcriptomic alterations across different cell types associated with age. We found that aged cardiomyocytes underwent a dramatic loss in cell numbers and profound fluctuations in transcriptional profiles. Via transcription regulatory network analysis, we identified FOXP1, a core transcription factor in organ development, as a key downregulated factor in aged cardiomyocytes, concomitant with the dysregulation of FOXP1 target genes associated with heart function and cardiac diseases. Consistently, the deficiency of FOXP1 led to hypertrophic and senescent phenotypes in human embryonic stem cell-derived cardiomyocytes. Altogether, our findings depict the cellular and molecular landscape of ventricular aging at the single-cell resolution, and identify drivers for primate cardiac aging and potential targets for intervention against cardiac aging and associated diseases.
衰老是心血管疾病的主要危险因素，也是老年人群的主要致死原因。然而，心脏衰老的细胞类型特异性变化还远不清楚。在这里，我们对年轻和老年食蟹猴的左心室进行了单细胞 RNA 测序分析，以定义与年龄相关的不同细胞类型的细胞组成变化和转录组改变。我们发现，衰老的心肌细胞数量急剧减少，转录谱发生深刻波动。通过转录调控网络分析，我们确定了 FOXP1，一种器官发育的核心转录因子，是衰老心肌细胞中关键下调因子，同时与心脏功能和心脏疾病相关的 FOXP1 靶基因失调。一致地，FOXP1 的缺乏导致人胚胎干细胞衍生的心肌细胞发生肥大和衰老表型。总的来说，我们的研究结果以单细胞分辨率描绘了心室衰老的细胞和分子图谱，并确定了灵长类动物心脏衰老的驱动因素和干预心脏衰老及相关疾病的潜在靶点。
