Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA, USA.
Department of Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, PA, USA.
Nat Methods. 2022 Oct;19(10):1306-1319. doi: 10.1038/s41592-022-01583-3. Epub 2022 Sep 5.
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.
造血人源化（hu）小鼠是模拟人类免疫系统作用的强大工具，广泛用于临床前研究和药物发现。然而，在 hu 小鼠中产生功能性人类 T 细胞群仍然具有挑战性，主要是由于人类和小鼠胸腺之间存在种属相关的差异。虽然植入人胎胸腺组织可以支持 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它们的广泛应用。在这里，我们描述了诱导多能干细胞（iPSC-胸腺）衍生的人胸腺类器官的组织工程，该工程可以支持功能多样的人类 T 细胞的从头生成。来自 iPSC-胸腺移植 hu 小鼠的 T 细胞可以介导细胞和体液免疫反应，包括在 T 细胞受体结合时引发强烈的促炎反应，抑制同种异体肿瘤移植物生长，并促进有效的 Ig 类别转换。我们的研究结果表明，植入 iPSC-胸腺的 hu 小鼠可以作为研究人类 T 细胞介导免疫的新型动物模型，并加速从动物研究中获得的发现向临床的转化。
