Modelling Sex Dependent Differences in Human Liver Disease using Stem Cell-Derived Models and Organ on a Chip Devices

使用干细胞衍生模型和芯片器件上的器官对人类肝脏疾病的性别依赖性差异进行建模

• 批准号: 2446049
• 金额: --
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2446049
• 关键词: Modelling; Sex; Dependent; Differences; Human

Metabolism syndrome directly influences different conditions such asdiabetes, heart disease or fat accumulation in individuals around the waist causing liver disease,for example, liver steatosis. Liver steatosis can progress into non-alcoholic fatty liver disease(NAFLD). NAFLD usually progresses into non-alcoholic steatohepatitis (NASH) causing tissuefibrosis and in 20% of the cases, cirrhosis of the liver. The susceptibility to NAFLD is impactedby excessive body fat and insulin insensitivity. Epidemiological studies show sex and agedifferences are important factors in developing fatty liver disease and metabolic syndrome,suggesting that sex hormones play important roles. Hence studying the effect of different sexhormones in different systems would cause an early risk prediction and would help to create amodel in the highly understudied scientific field.The studies show that age is an important factor in developing the NAFLD as premenopausalwomen are less likely to develop NAFLD than post-menopausal women due to sex hormonedeficiency. Moreover, androgens and oestrogens regulate lipid, glucose and cholesterolhomeostasis differently in men and women. Whilst testosterone protects males from fataccumulation in the liver, in females it promotes it. Oestrogens have an impact on theinflammatory response. In summary, sex hormones have different roles in different sexes thatare age-sensitive. Modelling sex differences would help us understand the progression of theliver disease, followed by new therapeutic strategies such as the precise dosage of hormonaltreatment.The aim of this project is to define the molecular basis of sex dependent differences in thedevelopment of non-alcoholic fatty liver disease as the basis for developing novel therapies tocorrect the aberrant phenotype. By using the novel NAFLD model that employs pluripotent stemcell derived hepatocyte like cells (HLCs) and exposing them to physiologically relevant levels ofandrogen, oestrogen and growth hormones, different environmental conditions ('fatty' or normaldiet) will be imposed. The interaction of hormone signaling and the development of steatosis willbe studied in vitro using a semi-automated platform developed in prof. Hay's lab (Centre ofRegenerative Medicine, University of Edinburgh), with a focus on key changes in liver cellbiology, including hepatic metabolism and function, cell viability, gene transcription and factorsecretion. Following in-depth analysis using bioinformatics coupled with target identification, thesex specific models developed from these studies will be further sophisticated using organ on achip systems. The gene regulatory datasets derived in static and perfused culture will be usedas a basis to restore hepatocyte homeostasis by reversing steatosis and/or reducinginflammatory gene expression. Studies will benefit from a close collaboration with an industrialpartner and an opportunity to work in different laboratories to gain experience in a broad rangeof methods and different working environments.

代谢综合征直接影响不同的条件，如糖尿病，心脏病或脂肪堆积在腰部周围的个人引起肝脏疾病，例如，肝脂肪变性。肝脏脂肪变性可以进展为非酒精性脂肪性肝病（NAFLD）。NAFLD通常进展为非酒精性脂肪性肝炎（NASH），引起组织纤维化，并且在20%的病例中，肝硬化。NAFLD的易感性受到过多的体脂和胰岛素不敏感性的影响。流行病学研究表明，性别和年龄差异是脂肪肝和代谢综合征发生的重要因素，提示性激素在其中起重要作用。因此，研究不同的性激素在不同系统中的作用将导致早期的风险预测，并将有助于在高度欠研究的科学领域建立模型。研究表明，年龄是发展NAFLD的重要因素，因为绝经前妇女不太可能发展NAFLD比绝经后妇女由于性激素缺乏。此外，雄激素和雌激素调节脂质，葡萄糖和胆固醇稳态在男性和女性不同。睾丸激素保护男性肝脏免受脂肪堆积，而女性则促进脂肪堆积。雌激素影响炎症反应。总之，性激素在不同性别中有不同的作用，对年龄敏感。建立性别差异模型将有助于我们了解肝病的进展，以及新的治疗策略，如精确的药物治疗剂量。本项目的目的是确定非酒精性脂肪性肝病发展中性别依赖性差异的分子基础，作为开发纠正异常表型的新疗法的基础。通过使用新的NAFLD模型，其采用多能干细胞衍生的肝细胞样细胞（HLC）并将它们暴露于生理相关水平的雄激素、雌激素和生长激素，将施加不同的环境条件（“脂肪”或正常饮食）。激素信号传导的相互作用和脂肪变性的发展将在体外研究使用在Hay教授的实验室（爱丁堡大学再生医学中心）开发的半自动化平台，重点是肝细胞生物学的关键变化，包括肝代谢和功能，细胞活力，基因转录和因子分泌。在使用生物信息学结合靶点识别进行深入分析之后，从这些研究中开发的性别特异性模型将使用器官芯片系统进一步完善。在静态和灌注培养中获得的基因调控数据集将被用作通过逆转脂肪变性和/或减少炎症基因表达来恢复肝细胞稳态的基础。研究将受益于与工业合作伙伴的密切合作，并有机会在不同的实验室工作，以获得广泛的方法和不同工作环境的经验。

项目成果

Protocol for automated production of human stem cell derived liver spheres.

• DOI: 10.1016/j.xpro.2021.100502
• 发表时间: 2021-06-18
• 期刊: STAR protocols
• 作者: Meseguer-Ripolles J;Kasarinaite A;Lucendo-Villarin B;Hay DC
• 通讯作者: Hay DC

Mathematical modelling of oxygen gradients in stem cell-derived liver tissue.

• DOI: 10.1371/journal.pone.0244070
• 发表时间: 2021
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Leedale JA;Lucendo-Villarin B;Meseguer-Ripolles J;Kasarinaite A;Webb SD;Hay DC
• 通讯作者: Hay DC