Secreted-frizzled-related protein 5 modulates calcium handling in human iPSC-cardiomyocytes. Secreted-frizzled-related protein 5 modulates calcium handling in human iPSC-cardiomyocytes

End-stage heart failure caused by myocardial injury is a leading cause of death in the developed world, with high prevalence and poor prognosis. Current therapies focus on attenuating cardiac remodeling after a cardiovascular event such as myocardial infarction or pressure overload, but no therapy is currently available to halt or reverse disease progression. Recent studies have suggested a cardioprotective function of the Wnt5a inhibitor secreted frizzled-related protein 5 (SFRP5) in preventing adverse cardiac remodeling. However, until now, the underlying molecular mechanisms of SFRP5 treatment in the human heart are not well understood. In this study, we investigated the mechanistic and functional consequences of SFRP5 by establishing knockout and overexpression models in human iPSC-derived cardiomyocytes. Transcriptome profiling and deep pathway analysis revealed an involvement of SFRP5 in the regulation of calcium handling, cardiac contraction, and apoptosis. Functional analysis of iPSC-cardiomyocytes by live-cell calcium imaging confirmed the regulatory role of SFRP5 on calcium homeostasis. Our study uncovered a novel role of SFRP5 as a modulator of calcium handling, providing a deeper molecular understanding of the cardioprotective role of SFRP5 in the human heart. Overall design: RNA-Seq

由心肌损伤诱发的终末期心力衰竭是发达国家的首要致死病因，具有高患病率与不良预后的双重特征。当前临床治疗手段主要聚焦于缓解心肌梗死、压力负荷过载等心血管事件后的心肌重构，但目前尚无疗法能够阻断甚至逆转疾病进展。近期研究表明，作为Wnt5a抑制剂的分泌型卷曲相关蛋白5（secreted frizzled-related protein 5，SFRP5）具有心脏保护功能，可预防不良心肌重构的发生。然而截至目前，SFRP5在人类心脏中发挥治疗作用的潜在分子机制仍未得到充分阐明。本研究通过在人类诱导多能干细胞（induced pluripotent stem cell，iPSC）衍生的心肌细胞中构建敲除与过表达模型，探究了SFRP5的机制与功能效应。转录组表达谱分析与深度通路分析显示，SFRP5参与调控钙离子稳态、心肌收缩与细胞凋亡过程。通过活细胞钙成像技术对iPSC源性心肌细胞进行功能验证，证实了SFRP5对钙离子稳态的调控作用。本研究揭示了SFRP5作为钙离子稳态调控因子的全新功能，为阐明其在人类心脏中的心脏保护作用提供了更深入的分子机制依据。整体实验设计：RNA测序（RNA-Seq）