超性心肌病相关的突变通过EGFR介导的膜信号传递驱动 stromal 激活
Jourdan K Ewoldt1, Miranda C Wang1,2,3, Micheal A McLellan1,2
1Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.
Science advances
|October 16, 2024
概括
这项研究揭示了超性心肌病 (HCM) 变异性心肌细胞驱动纤维细胞增殖和纤维化. 抑制这种信号通路可能为HCM提供治疗策略.
科学领域:
- 心血管生物学 心血管生物学
- 干细胞生物学 干细胞生物学
- 纤维化研究 纤维化研究
背景情况:
- 超性心肌病 (HCM) 涉及左心室加厚和纤维化,与sarcomere基因突变有关.
- 使用人类诱导的多能干细胞衍生心肌细胞 (hiPSC-CMs) 的现有体外模型缺乏检查纤维化中的多细胞相互作用.
研究的目的:
- 通过使用工程心脏微组织 (CMT) 调查细胞与细胞交叉交谈在HCM相关纤维化的作用.
- 确定驱动HCM纤维化的分子机制,重点关注对膜信号.
主要方法:
- 由MYH7变体的hiPSC-CM和野生型纤维细胞组成的工程心脏微组织 (CMT).
- 对原沉积,组织硬化,收缩性和纤维细胞增殖的分析.
- 单核RNA测序和条件介质分析以识别膜信号.
- 药理上抑制表皮生长因子受体氨酸激酶.
主要成果:
- 在CMT中,HCM变异的hiPSC-CM和纤维细胞呈现出增加的原沉积,组织硬化和减少的收缩性,这取决于纤维细胞增殖.
- 来自MYH7变异型心肌细胞的副质信号被确定为纤维细胞增殖的媒介.
- 埃尔洛提尼布化物治疗减弱了 stromal 激活.
- MYBPC3 变种CMT表现出明显的纤维状特征.
结论:
- 心肌细胞和纤维细胞之间通过膜介导的交叉交谈有助于HCM中的纤维变化.
- 通过膜信号来准纤维细胞激活,为HCM提供了潜在的治疗途径.
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