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对比转录基因分析验证了iPSC衍生的体外渐进性纤维化模型作为一种查工具,用于在全身性硬化症中发现和开发药物

Shyam Nathan¹, Yifei Wang¹, Matthew D'ambrosio²

¹Department of Immunology and Respiratory Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA.

Scientific reports

|October 18, 2024

概括

一种使用诱导多能干细胞衍生的介质细胞 (iSCAR) 的新型体外模型有效模仿系统性硬化症 (SSc) 纤维化. 这种类似痕的表型允许研究早期和晚期纤维化以及药物查.

科学领域:

生物医学工程生物医学工程
干细胞生物学干细胞生物学
类风湿病学类风湿病学

背景情况:

系统性硬化症 (SSc) 是一种具有挑战性的自身免疫性疾病,以纤维化为特征,由于疾病模型有限,影响了研究.
研究SSc需要捕捉其渐进性和细胞可塑性的模型.
多能干细胞衍生模型对于理解纤维菌异质性和选抗纤维菌药物至关重要.

研究的目的:

开发和描述一种新的体外模型,用于研究系统性硬化中的纤维化.
验证该模型在研究早期和晚期纤维化过程中的实用性.
评估该模型作为抗纤维菌药物查平台的潜力.

主要方法:

使用在模仿伤口的水凝上培养的诱导多能干细胞衍生中介细胞 (iSCAR) 来生成类似痕的表型.
RNA测序 (RNA-seq) 在iSCAR培养的早期 (48h) 和晚期 (13d) 阶段对转录组进行分析.
对系统性硬化症 (SSc) 汇编进行比较性转录基因分析,以确定常见的纤维化基因和途径.

主要成果:

该iSCAR模型成功地重复了关键的"痕相关"基因 (92%早期,85%迟).
早期的基因与缺氧,血管发育和糖解有关;晚期的基因与衰老有关.
该模型在验证两种抗纤维素化合物的有效性方面表现出了效果,一种针对晚期纤维化,另一种对早期和晚期都有效.

结论:

该iSCAR模型提供了一个强大的体外平台,用于研究系统性硬化症中纤维化的复杂机制.
这个模型有效地捕捉了早期和晚期纤维化表型,包括相关的基因表达.
作为一种查和验证新型抗纤维菌疗法的工具,iSCAR系统显示出显著的希望.

关键词:

细胞的可塑性细胞的可塑性基因表达分析基因表达分析在体外模型模型.渐进性纤维化渐进性纤维化系统性硬化症系统性硬化症

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