De novo construction of T cell compartment in humanized mice engrafted with iPSC-derived thymus organoids
De novo construction of T cell compartment in humanized mice engrafted with iPSC-derived thymus organoids
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DOI：
10.1038/s41592-022-01583-3
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发表时间：
2022-09-05
期刊：
影响因子：
48
通讯作者：
Fan, Yong
中科院分区：
文献类型：
--
作者：
Zeleniak, Ann;Wiegand, Connor;Fan, Yong
造血系统人源化小鼠是模拟人体免疫系统功能的有力工具，广泛应用于临床前研究和药物开发。然而，在hu小鼠中产生功能性人类T细胞区室仍然具有挑战性，主要是由于人类和小鼠胸腺之间的物种相关差异。虽然移植人胎儿胸腺组织可以支持hu小鼠中强大的T细胞发育，但组织稀缺和伦理问题限制了其广泛使用。在这里，我们描述了从诱导型多能干细胞（iPSC-胸腺）的人胸腺类器官的组织工程，其可以支持功能性人T细胞的不同群体的从头生成。iPSC-胸腺-移植的hu小鼠的T细胞可以介导细胞和体液免疫应答，包括在T细胞受体接合上建立稳健的促炎应答，抑制同种异体肿瘤移植物生长和促进有效的IG类别转换。我们的研究结果表明，植入iPSC-胸腺的hu小鼠可以作为一种新的动物模型来研究人类T细胞介导的免疫，并加速将动物研究的结果转化为临床。人类胸腺类器官的移植支持在人源化小鼠模型中从头开发功能性人类T细胞区室。
Hematopoietic humanized (hu) mice are powerful tools for modeling the action of human immune system and are widely used for preclinical studies and drug discovery. However, generating a functional human T cell compartment in hu mice remains challenging, primarily due to the species-related differences between human and mouse thymus. While engrafting human fetal thymic tissues can support robust T cell development in hu mice, tissue scarcity and ethical concerns limit their wide use. Here, we describe the tissue engineering of human thymus organoids from inducible pluripotent stem cells (iPSC-thymus) that can support the de novo generation of a diverse population of functional human T cells. T cells of iPSC-thymus-engrafted hu mice could mediate both cellular and humoral immune responses, including mounting robust proinflammatory responses on T cell receptor engagement, inhibiting allogeneic tumor graft growth and facilitating efficient Ig class switching. Our findings indicate that hu mice engrafted with iPSC-thymus can serve as a new animal model to study human T cell-mediated immunity and accelerate the translation of findings from animal studies into the clinic.Engraftment of human thymic organoids supports de novo development of a functional human T cell compartment in a humanized mouse model.