Engineered Platforms for Maturing Pluripotent Stem Cell-Derived Liver Cells for Disease Modeling.
Engineered Platforms for Maturing Pluripotent Stem Cell-Derived Liver Cells for Disease Modeling.
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DOI：
10.1016/j.jcmgh.2023.01.013
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发表时间：
2023
影响因子：
7.2
通讯作者：
Khetani, Salman R.
中科院分区：
文献类型：
--
作者：
Yuan, Yang;Cotton, Kristen;Samarasekera, Dinithi;Khetani, Salman R.
多种肝脏疾病（例如乙型/丙型肝炎病毒、酒精/非酒精性脂肪肝、疟疾、单基因疾病和药物性肝损伤）对全球死亡率和发病率有显着影响。肝功能的物种特异性差异限制了使用动物来充分阐明/预测人类结果；因此，体外人类肝脏模型用于基础和转化研究，以补充动物研究。然而，原代人肝细胞供应短缺，并且在活力/质量方面表现出供体与供体之间的差异。相比之下，由诱导多能干细胞和胚胎干细胞分化而来的人类肝细胞样细胞（HLC）是一种近乎无限的细胞资源，保留了患者/捐赠者的遗传背景；然而，传统方案会产生不成熟的表型。使用先进技术可以显着改善 HLC 的成熟，例如精确控制细胞间相互作用的蛋白质微图案、控制大小的球体、具有多种细胞类型和层的类器官、空间控制细胞群的 3 维生物打印、用于自动营养交换并通过可溶性因子梯度诱导肝脏分区的微流体装置，以及对 HLC 进行遗传修饰以加速和增强成熟的合成生物学。在这里，我们介绍了具有代表性的先进 HLC 成熟平台的设计特征和表征，然后讨论了 HLC 在建模各种肝脏疾病中的用途。最后，我们讨论推动该领域向前发展的理想进展。我们预计，随着这一领域的不断进步，多能干细胞衍生的肝脏模型将在临床前药物开发中更早地提供与人类相关的数据，并减少动物的使用，帮助阐明肝脏疾病机制，以发现有效和安全的治疗方法，并可作为针对患有终末期肝衰竭的患者的基于细胞的疗法。
Several liver diseases (eg, hepatitis B/C viruses, alcoholic/nonalcoholic fatty liver, malaria, monogenic diseases, and drug-induced liver injury) significantly impact global mortality and morbidity. Species-specific differences in liver functions limit the use of animals to fully elucidate/predict human outcomes; therefore, in vitro human liver models are used for basic and translational research to complement animal studies. However, primary human liver cells are in short supply and display donor-to-donor variability in viability/quality. In contrast, human hepatocyte-like cells (HLCs) differentiated from induced pluripotent stem cells and embryonic stem cells are a near infinite cell resource that retains the patient/donor’s genetic background; however, conventional protocols yield immature phenotypes. HLC maturation can be significantly improved using advanced techniques, such as protein micropatterning to precisely control cell-cell interactions, controlled sized spheroids, organoids with multiple cell types and layers, 3-dimensional bioprinting to spatially control cell populations, microfluidic devices for automated nutrient exchange and to induce liver zonation via soluble factor gradients, and synthetic biology to genetically modify the HLCs to accelerate and enhance maturation. Here, we present design features and characterization for representative advanced HLC maturation platforms and then discuss HLC use for modeling various liver diseases. Lastly, we discuss desirable advances to move this field forward. We anticipate that with continued advances in this space, pluripotent stem cell–derived liver models will provide human-relevant data much earlier in preclinical drug development and reduce animal usage, help elucidate liver disease mechanisms for the discovery of efficacious and safe therapeutics, and be useful as cell-based therapies for patients suffering from end-stage liver failure.
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影响因子：
5.4
作者：
GUIDOTTI, LG;MATZKE, B;CHISARI, FV
通讯作者：
CHISARI, FV
DOI：
10.3390/pathogens3020377
发表时间：
2014-04-23
期刊：
Pathogens (Basel, Switzerland)
影响因子：
--
作者：
Inuzuka T;Takahashi K;Chiba T;Marusawa H
通讯作者：
Marusawa H
影响因子：
16.6
作者：
Boon, Ruben;Kumar, Manoj;Verfaillie, Catherine M.
通讯作者：
Verfaillie, Catherine M.
影响因子：
2.6
作者：
Fattahi, Faranak;Asgari, Samira;Baharvand, Hossein
通讯作者：
Baharvand, Hossein
影响因子：
5.6
作者：
Freyer, Nora;Greuel, Selina;Zeilinger, Katrin
通讯作者：
Zeilinger, Katrin