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Transcriptomic characterization of culture-associated changes in murine and human precision-cut tissue slices

机译：小鼠和人精密切割组织切片文化相关变化的转录组特征

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摘要

Our knowledge of complex pathological mechanisms underlying organ fibrosis is predominantly derived from animal studies. However, relevance of animal models for human disease is limited; therefore, an ex vivo model of human precision-cut tissue slices (PCTS) might become an indispensable tool in fibrosis research and drug development by bridging the animal-human translational gap. This study, presented as two parts, provides comprehensive characterization of the dynamic transcriptional changes in PCTS during culture by RNA sequencing. Part I investigates the differences in culture-induced responses in murine and human PCTS derived from healthy liver, kidney and gut. Part II delineates the molecular processes in cultured human PCTS generated from diseased liver, kidney and ileum. We demonstrated that culture was associated with extensive transcriptional changes and impacted PCTS in a universal way across the organs and two species by triggering an inflammatory response and fibrosis-related extracellular matrix (ECM) remodelling. All PCTS shared mRNA upregulation of IL-11 and ECM-degrading enzymes MMP3 and MMP10. Slice preparation and culturing activated numerous pathways across all PCTS, especially those involved in inflammation (IL-6, IL-8 and HMGB1 signalling) and tissue remodelling (osteoarthritis pathway and integrin signalling). Despite the converging effects of culture, PCTS display species-, organ- and pathology-specific differences in the regulation of genes and canonical pathways. The underlying pathology in human diseased PCTS endures and influences biological processes like cytokine release. Our study reinforces the use of PCTS as an ex vivo fibrosis model and supports future studies towards its validation as a preclinical tool for drug development.
机译：我们对器官纤维化的复杂病理机制的了解主要来自动物研究。然而，人类疾病的动物模型的相关性有限;因此，通过弥合动物人类平移差距，人精密切割组织切片（PCTS）的前体内模型可能成为纤维化研究和药物开发中不可或缺的工具。本研究呈现为两部分，通过RNA测序提供培养过程中PCTS的动态转录变化的综合表征。第一部分研究了来自健康肝，肾和肠道的小鼠和人体PCT的培养诱导的反应的差异。第二部分描绘了患有患病肝，肾和回肠产生的培养人体PCT中的分子过程。我们证明，通过引发炎症反应和纤维化相关的细胞外基质（ECM）重塑，培养培养与广泛的转录变化，并以普遍的方式影响PCT和两种物种。所有PCTS共享MRNA上调IL-11和ECM降解酶MMP3和MMP10。切片制备和培养在所有PCT中激活了许多途径，尤其是涉及炎症（IL-6，IL-8和HMGB1信号传导）和组织重塑（骨关节炎途径和整合素信号传导）的途径。尽管培养物的融合作用，PCTS显示出物种，器官和病理学特异性差异在基因和规范途径的调节中。人类患病PCT的潜在病理持续并影响细胞因子释放等生物过程。我们的研究强化了PCTS作为前体内纤维化模型的使用，并支持未来的研究，以验证为临床前工具进行药物开发。

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  • 来源
    《Archives of Toxicology》 |2019年第12期|共35页
  • 作者

    Bigaeva Emilia; Gore Emilia; Simon Eric; Zwick Matthias; Oldenburger Anouk; de Jong Koert P.; Hofker Hendrik S.; Schlepuetz Marco; Nicklin Paul; Boersema Miriam; Rippmann Joerg F.; Olinga Peter;

  • 作者单位

    Univ Groningen Dept Pharmaceut Technol &

    Biopharm Antonius Deusinglaan 1 NL-9713 AV Groningen;

    Univ Groningen Dept Pharmaceut Technol &

    Biopharm Antonius Deusinglaan 1 NL-9713 AV Groningen;

    Boehringer Ingelheim Pharma GmbH &

    Co KG Computat Biol Birkendorfer Str 65 D-88397 Biberach;

    Boehringer Ingelheim Pharma GmbH &

    Co KG Computat Biol Birkendorfer Str 65 D-88397 Biberach;

    Boehringer Ingelheim Pharma GmbH &

    Co KG Cardiometab Dis Res Birkendorfer Str 65 D-88397;

    Univ Groningen Univ Med Ctr Groningen Dept Hepatopancreatobiliary Surg &

    Liver Transpla Hanzepl;

    Univ Groningen Univ Med Ctr Groningen Dept Surg Hanzepl 1 NL-9713 GZ Groningen Netherlands;

    Boehringer Ingelheim Pharma GmbH &

    Co KG Resp Dis Birkendorfer Str 65 D-88397 Biberach Germany;

    Boehringer Ingelheim Pharma GmbH &

    Co KG Res Beyond Borders Birkendorfer Str 65 D-88397 Biberach;

    Univ Groningen Dept Pharmaceut Technol &

    Biopharm Antonius Deusinglaan 1 NL-9713 AV Groningen;

    Boehringer Ingelheim Pharma GmbH &

    Co KG Cardiometab Dis Res Birkendorfer Str 65 D-88397;

    Univ Groningen Dept Pharmaceut Technol &

    Biopharm Antonius Deusinglaan 1 NL-9713 AV Groningen;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 毒物学（毒理学）;
  • 关键词

    Precision-cut tissue slices; Fibrosis; Inflammation; Human tissue; RNA sequencing; Ingenuity pathway analysis;

    机译：精密切割组织切片;纤维化;炎症;人体组织;RNA测序;熟智能途径分析;

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