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机械拉伸下的ERRγ激动剂通过成熟表现出人工心脏组织的缩性心肌病表型

Yuya Fujiwara¹, Kenji Miki², Kohei Deguchi³

¹Center for iPS Cells Research and Application, Kyoto University, Kyoto, Japan; Takeda-CiRA Joint Program, Fujisawa, Japan.

Stem cell reports

|October 6, 2023

概括

这项研究增强了工程心脏组织 (ECT) 成熟度,用于过度缩小心肌病 (HCM) 建模. 将ERRγ激活与机械拉伸相结合,可以提高心脏模型中疾病表型的准确性.

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
疾病建模疾病建模

背景情况:

来自人类诱导的多能干细胞衍生的心肌细胞的工程心脏组织 (ECT) 为心脏病研究提供了一个有前途的平台.
当前ECT模型中的组织不成熟性限制了它们在准确建模复杂心脏病,如多变性心肌病 (HCM) 的稳健性.

研究的目的:

建立一种加速ECT成熟的方法,以改善HCM中恶性 (MYH7 R719Q) 和非恶性 (MYBPC3 G115*) 致病性sarcomere基因突变的建模.
研究ERRγ激动剂 (T112) 结合机械拉伸对ECT成熟和表型表达的影响.

主要方法:

通过使用ERRγ激动剂 (T112) 和机械拉伸 (10%延长) 来成熟工程心脏组织 (ECT).
该研究比较了在新成熟协议下携带MYH7 R719Q和MYBPC3 G115*突变的成熟ECT的表型特征.

主要成果:

使用10%延长刺激的T112治疗导致了更有组织和成熟的ECT.
成熟的MYH7 R719Q ECT表现出全面的HCM表型,包括过度缩,过度收缩,腹功能障碍,肌纤维细胞 misalignment,纤维化和甘油性激活.
成熟的MYBPC3 G115* ECT显示出有限的表型,主要是缩,在增强成熟协议下最明显.

结论:

结合ERRγ激活和机械刺激,可显著提高ECT成熟度.
这种改进的成熟协议使得HCM表型在体外表现得更加准确和全面,包括非心肌细胞激活.
开发的方法提供了一个更强大的平台来研究HCM病原体和潜在的测试治疗干预措施.

关键词:

疾病建模疾病建模工程心脏组织的工程心脏组织.与雌激素相关的玛受体是雌激素相关的受体.纤维化纤维化纤维化过度缩性心肌病变性是一种心肌疾病.成熟成熟成熟成熟成熟机械应力机械应力机械应力萨尔科默尔基因突变的突变来自干细胞的心肌细胞.

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