Stem cell-based multi-tissue platforms to model human autoimmune diabetes.
Stem cell-based multi-tissue platforms to model human autoimmune diabetes.
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DOI：
10.1016/j.molmet.2022.101610
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发表时间：
2022-12
影响因子：
8.1
通讯作者：
V. Parent, Audrey
中科院分区：
文献类型：
--
作者：
Leavens, Karla F.;Alvarez-Dominguez, Juan R.;Vo, Linda T.;Russ, Holger A.;V. Parent, Audrey
关键词：
1型糖尿病（T1D）是一种自身免疫性疾病，其中胰腺胰岛素生成β细胞被免疫系统特异性破坏。由于缺乏能够再现该疾病复杂性和异质性的适当模型，对人类T1D的发生和进展的理解一直受到阻碍。结合多种人类多能干细胞（hPSC）衍生组织的平台的发展来模拟T1D的不同方面，有可能为人类疾病的病因和发病机制提供关键的新见解。在这篇综述中，我们总结了hPSC分化方法的现状，以产生与T1D相关的细胞类型和组织，特别关注胰岛细胞、T细胞和胸腺上皮。我们介绍了目前的应用以及使用这些hpsc衍生细胞进行疾病建模的局限性，并讨论了优化结合多种细胞类型的平台以模拟人类T1D的努力。最后，我们概述了仍然存在的挑战，并强调了加快这一新兴研究领域进展所需的未来改进。最近在重编程方法以创建患者特异性诱导多能干细胞系（iPSCs）、基因组工程技术以有效修饰多能干细胞的DNA以及指导其分化为成熟细胞类型的方案方面的进展，使干细胞衍生物的使用能够准确地模拟人类疾病。虽然在人类T1D中发生的复杂相互作用可以用这些衍生物建模之前仍然存在挑战，但结合hpsc衍生的β细胞和免疫细胞的实验已经为这些细胞在T1D背景下如何相互作用提供了令人兴奋的见解，支持了这种方法的可行性。
Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic insulin-producing β cells are specifically destroyed by the immune system. Understanding the initiation and progression of human T1D has been hampered by the lack of appropriate models that can reproduce the complexity and heterogeneity of the disease. The development of platforms combining multiple human pluripotent stem cell (hPSC) derived tissues to model distinct aspects of T1D has the potential to provide critical novel insights into the etiology and pathogenesis of the human disease. In this review, we summarize the state of hPSC differentiation approaches to generate cell types and tissues relevant to T1D, with a particular focus on pancreatic islet cells, T cells, and thymic epithelium. We present current applications as well as limitations of using these hPSC-derived cells for disease modeling and discuss efforts to optimize platforms combining multiple cell types to model human T1D. Finally, we outline remaining challenges and emphasize future improvements needed to accelerate progress in this emerging field of research. Recent advances in reprogramming approaches to create patient-specific induced pluripotent stem cell lines (iPSCs), genome engineering technologies to efficiently modify DNA of hPSCs, and protocols to direct their differentiation into mature cell types have empowered the use of stem cell derivatives to accurately model human disease. While challenges remain before complex interactions occurring in human T1D can be modeled with these derivatives, experiments combining hPSC-derived β cells and immune cells are already providing exciting insight into how these cells interact in the context of T1D, supporting the viability of this approach.
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