In vitro and in silico approaches to engineering three-dimensional biological tissues and organoids
In vitro and in silico approaches to engineering three-dimensional biological tissues and organoids
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DOI：
10.1098/rsfs.2022.0046
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发表时间：
2022-08-12
期刊：
影响因子：
4.4
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中科院分区：
文献类型：
--
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尽管二维（2D）细胞模型和动物模型在增加对细胞生物学的基本理解方面所发挥的核心作用是无可争议的，但两者都不能准确地概括人体组织的生理学及其对不同扰动的药理学反应。例如，在动物研究中，高达50%的引起人类肝损伤的化合物没有显示出类似的作用[1]。对这些缺陷的日益认识已经导致开发了一系列人类组织的三维（3D）细胞培养模型，其包括基于特定人类组织的已知细胞组成的单细胞和多细胞模型，以及组织干细胞衍生的类器官，在此统称为微组织。这些具有巨大的潜力，有助于阐明人类生理学，疾病机制及其安全治疗[2]。3D模型的开发受到几个主要挑战的限制。药物发现、细胞治疗和个性化医疗应用需要新技术来复制生物物理细胞生长条件，增强微组织处理的可重复性，重要的是，提供分析选项来捕获可能产生的细胞结构的复杂性。这需要在物理科学领域持续的跨学科合作和创新。事实上，许多常规研究方法从2D到3D的转换是具有挑战性的。这个特别版展示了当前的研究，旨在解决与开发3D组织相关的一些挑战。这些贡献来自MRC资助的网络3DBioNet的成员，该网络旨在建立来自工业界和学术界的多学科科学家团队，他们共同拥有开发3D微组织所需的各种技能。如下所述，这五篇特色文章涵盖了类器官发育的实验方法[3]，使用3D支架促进伤口愈合[4]，从2D显微镜图像重建和分析3D结构的软件[5]，量化3D类器官中细胞数量的方法[6]以及数学和计算建模[7]。Bhargava等人的文章关注神经退行性疾病（NDD）的体外模型，并越来越意识到其患病率可能随着人口年龄的增长而增加。[3]突出了人类类器官开发和应用的临床和治疗驱动因素。虽然动物模型提供了关于NDD发病机制和病理生物学的有用信息，但它们的使用受到限制，因为它们经常过度表达突变蛋白，模糊了关于NDD发作和进展的细节。这些因素，再加上人们对动物实验相关伦理问题的认识提高，以及使用NDD患者适当组织的技术困难，正在推动涉及诱导多能干细胞（iPSC）的体外模型的发展，以研究NDD的发病和进展。iPSC具有自我更新特性，可以分化成多种细胞类型，包括运动神经元、星形胶质细胞和小胶质细胞，因此可以用于理解NDD。在他们的文章中，Bhargava et al. [3]对现有的使用iPSCs研究NDD的体外方法进行全面综述，重点关注2D和3D技术的优缺点。
Although the central roles played by two-dimensional (2D) cell models and animal models in increasing fundamental understanding of cell biology are undisputed, neither can accurately recapitulate the physiology of human tissues and their pharmacological responses to different perturbations. For example, up to 50% of compounds eliciting liver injury in man do not show similar effects in animal studies [1]. Increasing awareness of these deficiencies has led to the development of a range of three-dimensional (3D) cell culture models of human tissues that include unicellular and multi-cellular models based on known cellular compositions of particular human tissues, and tissue stem cell-derived organoids, collectively termed here microtissues. These have enormous potential for helping to elucidate human physiology, mechanisms of disease and their safe treatment [2]. Exploitation of 3D models is limited by several major challenges. Drug discovery, cell therapy and personalized medicine applications require new technologies that replicate biophysical cell growth conditions, enhance the reproducibility of microtissue handling and, importantly, provide analytical options that capture the complexity of the cellular structures that can be generated. This requires sustained interdisciplinary collaborations and innovations in the physical sciences. Indeed, the translation of many routine research methods from 2D to 3D is challenging. This special edition showcases current research which aims to tackle some of the challenges associated with developing 3D tissues. The contributions come from members of an MRC-funded network 3DBioNet which aims to establish multi-disciplinary teams of scientists from industry and academia who together possess the diverse skills needed to develop 3D microtissues. As explained below, the five, featured articles span experimental methods for organoid development [3], the use of 3D scaffolds to promote wound healing [4], software for reconstructing and analysing 3D structures from 2D microscopy images [5], methods for quantifying cell numbers in 3D organoids [6] and mathematical and computational modelling [7]. With its focus on in vitro models of neurodegenerative diseases (NDDs) and increasing awareness that their prevalence is likely to increase as populations age, the article by Bhargava et al.[3] highlights the clinical and therapeutic drivers for the development and application of human organoids. While animal models provide useful information about the pathogenesis and pathobiology of NDDs, their use is limited as they often overexpress mutant proteins, obscuring details about the onset and progression of NDDS. These factors, combined with increased awareness of the ethical issues associated with animal experiments and technical difficulties with using appropriate tissue from NDD patients, are driving the development of in vitro models involving induced pluripotent stem cells (iPSCs) to study NDD onset and progression. iPSCs have self-renewal properties and can differentiate into multiple cell types, including motor neurons, astrocytes and microglia and, as such, can be used to understand NDDs. In their article, Bhargava et al.[3] provide a comprehensive review of existing in vitro methods for using iPSCs to study NDDs, focusing on the pros and cons of 2D and 3D techniques.
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影响因子：
2
作者：
Celora, Giulia L.;Bader, Samuel B.;Byrne, Helen M.
通讯作者：
Byrne, Helen M.
干细胞衍生的模型，以提高对人类药物诱导的肝损伤的机械理解和预测。
DOI：
10.1002/hep.28886
发表时间：
2017-02
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Goldring C;Antoine DJ;Bonner F;Crozier J;Denning C;Fontana RJ;Hanley NA;Hay DC;Ingelman-Sundberg M;Juhila S;Kitteringham N;Silva-Lima B;Norris A;Pridgeon C;Ross JA;Young RS;Tagle D;Tornesi B;van de Water B;Weaver RJ;Zhang F;Park BK
通讯作者：
Park BK
影响因子：
3.5
作者：
Collis, Joe;Connor, Anthony J.;Hubbard, Matthew E.
通讯作者：
Hubbard, Matthew E.
影响因子：
4.4
作者：
Leedale, Joseph A.;Kyffin, Jonathan A.;Bearon, Rachel N.
通讯作者：
Bearon, Rachel N.
影响因子：
4.4
作者：
Hyndman, Lauren;McKee, Sean;McGinty, Sean
通讯作者：
McGinty, Sean