Versican Promotes Cardiomyocyte Proliferation and Cardiac Repair
Versican Promotes Cardiomyocyte Proliferation and Cardiac Repair
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DOI：
10.1161/circulationaha.123.066298
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发表时间：
2024-03-26
期刊：
影响因子：
37.8
通讯作者：
Nie，Yu
中科院分区：
文献类型：
--
作者：
Feng，Jie;Li，Yandong;Nie，Yu
成年哺乳动物的心脏不能再生，而新生儿的心脏主要通过先前存在的心肌细胞的增殖维持短暂的再生能力。心肌损伤后的新生心脏再生伴随着心脏成纤维细胞的扩张和细胞外基质的成分变化。这些变化是否以及如何影响心肌细胞增殖和心脏再生仍有待研究。METHODS我们使用心尖切除术和心肌梗死手术模型，在新生儿和成年小鼠研究细胞外基质成分参与心脏损伤后再生。单细胞RNA测序和液相色谱-质谱分析用于多功能蛋白聚糖鉴定。使用小鼠品系Col 1a 2 - 2A-CreER和Vcanfl/fl实现心脏成纤维细胞特异性Vcan缺失。通过Western印迹、免疫染色和定量逆转录聚合酶链反应评估与多功能蛋白聚糖作用相关的分子信号通路。Masson三色染色和超声心动图分别评价心脏纤维化和心功能。心肌成纤维细胞来源的细胞外基质成分ATSVersican在新生心肌损伤后上调，并促进心肌细胞增殖。条件性敲除心脏成纤维细胞中的Vcanin可降低心肌细胞增殖并损害新生心脏再生。在成年小鼠中，心肌梗死后心肌内注射多功能蛋白聚糖增强心肌细胞增殖，减少纤维化，改善心脏功能。此外，多功能蛋白聚糖增强了人诱导多能干细胞衍生的心肌细胞的增殖。从机制上讲，多能蛋白聚糖激活整合素β1和下游信号分子，包括ERK 1/2和Akt，从而促进心肌细胞增殖和心脏repair.CONCLUSIONSOUR研究确定多能蛋白聚糖作为心脏成纤维细胞衍生的促增殖蛋白聚糖，并阐明多能蛋白聚糖在促进成人心脏修复中的作用。这些发现突出了其作为缺血性心脏病治疗因子的潜力。
BACKGROUNDThe adult mammalian heart is incapable of regeneration, whereas a transient regenerative capacity is maintained in the neonatal heart, primarily through the proliferation of preexisting cardiomyocytes. Neonatal heart regeneration after myocardial injury is accompanied by an expansion of cardiac fibroblasts and compositional changes in the extracellular matrix. Whether and how these changes influence cardiomyocyte proliferation and heart regeneration remains to be investigated.METHODSWe used apical resection and myocardial infarction surgical models in neonatal and adult mice to investigate extracellular matrix components involved in heart regeneration after injury. Single-cell RNA sequencing and liquid chromatography–mass spectrometry analyses were used for versican identification. Cardiac fibroblast–specificVcandeletion was achieved using the mouse strainsCol1a2-2A-CreERandVcanfl/fl. Molecular signaling pathways related to the effects of versican were assessed through Western blot, immunostaining, and quantitative reverse transcription polymerase chain reaction. Cardiac fibrosis and heart function were evaluated by Masson trichrome staining and echocardiography, respectively.RESULTSVersican, a cardiac fibroblast–derived extracellular matrix component, was upregulated after neonatal myocardial injury and promoted cardiomyocyte proliferation. Conditional knockout ofVcanin cardiac fibroblasts decreased cardiomyocyte proliferation and impaired neonatal heart regeneration. In adult mice, intramyocardial injection of versican after myocardial infarction enhanced cardiomyocyte proliferation, reduced fibrosis, and improved cardiac function. Furthermore, versican augmented the proliferation of human induced pluripotent stem cell–derived cardiomyocytes. Mechanistically, versican activated integrin β1 and downstream signaling molecules, including ERK1/2 and Akt, thereby promoting cardiomyocyte proliferation and cardiac repair.CONCLUSIONSOur study identifies versican as a cardiac fibroblast–derived pro-proliferative proteoglycan and clarifies the role of versican in promoting adult cardiac repair. These findings highlight its potential as a therapeutic factor for ischemic heart diseases.