致心律失常性右室心肌病中脂肪细胞的起源

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a chronic inherited cardiomyopathy, which is mostly resulted from mutation of desmosomal genes and characterized by ventricular arrhythmias, ventricular dilation, cardiac fibrosis and adipocyte accumulation in ventricular walls. Deletion of DSP in cardiomyocytes leads to ARVC in mice. Previous study based on in vitro experiments showed that cardiomyocyte cell lines could transdifferentiate into adipocytes when DSP was inhibited. However, in vivo genetic lineage tracing study demonstrated that cardiomyocytes contributed only to the subepicardial adipocytes, but not to the ones accumulated in the ventricular walls in ARVC hearts. Thus far, the main origin and pathogenesis of ARVC adipocytes in ventricular walls are still unknown. Our previous work has showed that the adipocytes in ventricular walls in normal adult heart are from Sox9+ stromal cells. Given previous in vitro studies, we speculate that ARVC adipocytes in the ventricular walls are still derived from Sox9+ stromal cells. We will illustrate the origin of ARVC adipocytes and the regulatory mechanism, by utilizing dual-system mediated lineage tracing.

致心律失常性右室心肌病（arrhythmogenic right ventricular cardiomyopathy，ARVC）是一种慢性遗传性心肌病，大多由桥粒基因突变导致，伴随着心室心律失常，心室扩张，心脏纤维化以及心室壁中大量脂肪积聚等症状。在小鼠心肌细胞中敲除DSP基因可以导致ARVC疾病的发生。前人体外实验证明心肌细胞系中抑制DSP可以导致心肌细胞向脂肪细胞的转分化，然而体内谱系示踪实验证明心肌细胞只贡献了ARVC心外膜下的脂肪细胞，心室壁中脂肪细胞并不是心肌细胞来源。目前，ARVC心室壁脂肪细胞的主要起源和发生机制仍然是未知的。我们前期工作证明了正常成体心脏中心室壁脂肪细胞起源于心脏中Sox9+基质细胞。结合前人体外实验结果，我们推测ARVC心室壁中积聚的脂肪细胞仍然主要起源于Sox9+基质细胞。我们将利用双系统介导的谱系示踪技术，阐明ARVC脂肪起源及其调控机制。

心律失常性心肌病（Arrhythmogenic cardiomyopathy, ACM）是最常见的遗传性心肌病之一，其特征是心肌组织广泛地被纤维脂肪组织替代。然而，ACM中心脏脂肪细胞的细胞起源还没有研究清楚。阐明ACM心脏脂肪细胞的来源对于揭示其病理过程和发病机制有着非常重要的意义，并且可以为其提供潜在的治疗靶点。因此，我们通过在心肌细胞中特异敲除DSP桥粒基因来构建ACM疾病小鼠模型，同时在小鼠模型中检测了多种类型心脏细胞的命运变化。研究结果显示心脏中SOX9+，PDGFRa+和PDGFRb+基质细胞是ACM脂肪细胞的祖细胞，而平滑肌细胞和心肌细胞并不是ACM脂肪细胞的起源。最后，我们发现Bmp4分子在ACM模型小鼠心脏中高表达，并且在体外可促进心脏基质细胞向脂肪细胞的分化。