Human iPS derived progenitors bioengineered into liver organoids using an inverted colloidal crystal poly (ethylene glycol) scaffold.
Human iPS derived progenitors bioengineered into liver organoids using an inverted colloidal crystal poly (ethylene glycol) scaffold.
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DOI：
10.1016/j.biomaterials.2018.07.043
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发表时间：
2018-11
期刊：
影响因子：
14
通讯作者：
Rashid ST
中科院分区：
文献类型：
--
作者：
Ng SS;Saeb-Parsy K;Blackford SJI;Segal JM;Serra MP;Horcas-Lopez M;No DY;Mastoridis S;Jassem W;Frank CW;Cho NJ;Nakauchi H;Glenn JS;Rashid ST
从诱导多能干细胞（iPSC）产生人类类器官为发育生物学，疾病建模和细胞治疗提供了令人兴奋的可能性。实现这些目标的重大进展受到依赖于动物来源的基质（例如Matrigel）、永生化细胞系和难以控制或缩放的所得结构的阻碍。为了解决这些挑战，我们的目标是使用倒置胶体晶体（ICC）开发一个完全定义的肝脏类器官平台，其三维机械特性可以被工程化以重现人类发育过程中肝祖细胞所感知的细胞外生态位。iPSC衍生的肝祖细胞（IH）在ICC支架中形成类器官最佳，所述ICC支架在模拟肝芽形成的两步过程中由涂覆有I型胶原的140 μm直径孔构建。与2D和3D对照相比，所得类器官在形态、基因表达、蛋白质分泌、药物代谢和病毒感染方面更接近成人组织，并且在植入免疫缺陷小鼠的肝脏后可以整合、血管形成和发挥功能。对基础机制的初步研究强调了TGFβ和hedgehog信号通路的重要性。功能相关性与可调机械性能的结合使我们提出这种生物工程平台非常适合于一系列未来的机械和临床类器官相关应用。
Generation of human organoids from induced pluripotent stem cells (iPSCs) offers exciting possibilities for developmental biology, disease modelling and cell therapy. Significant advances towards those goals have been hampered by dependence on animal derived matrices (e.g. Matrigel), immortalized cell lines and resultant structures that are difficult to control or scale. To address these challenges, we aimed to develop a fully defined liver organoid platform using inverted colloid crystal (ICC) whose 3-dimensional mechanical properties could be engineered to recapitulate the extracellular niche sensed by hepatic progenitors during human development. iPSC derived hepatic progenitors (IH) formed organoids most optimally in ICC scaffolds constructed with 140 μm diameter pores coated with type I collagen in a two-step process mimicking liver bud formation. The resultant organoids were closer to adult tissue, compared to 2D and 3D controls, with respect to morphology, gene expression, protein secretion, drug metabolism and viral infection and could integrate, vascularise and function following implantation into livers of immune-deficient mice. Preliminary interrogation of the underpinning mechanisms highlighted the importance of TGFβ and hedgehog signalling pathways. The combination of functional relevance with tuneable mechanical properties leads us to propose this bioengineered platform to be ideally suited for a range of future mechanistic and clinical organoid related applications.
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