<br>快速生成 hPSC 衍生的高内皮小静脉类器官，具有体内异位淋巴组织能力,Advanced Materials

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快速生成 hPSC 衍生的高内皮小静脉类器官，具有体内异位淋巴组织能力
Advanced Materials ( IF 27.4 ) Pub Date : 2024-02-02 , DOI: 10.1002/adma.202308760
Xichi Wang _{1,

2} , Xiaofei Li _{1,

3} , Jing Zhao _{1,

3} , Yi Li ₁ , Su Ryon Shin ₁ , Giovanni Ligresti ₄ , Alex H M Ng _{5,

6} , Jonathan S Bromberg ₇ , George Church _{5,

6} , Dario R Lemos _{1,

2,

8} , Reza Abdi _{1,

2,

3,

8}

Affiliation

制造模拟淋巴结（LN）和三级淋巴结构（TLS）的植入式淋巴结构的生物工程策略可以放大适应性免疫反应，用于癌症免疫治疗等治疗应用。迄今为止，没有任何方法导致高位内皮小静脉（HEV）的持续形成，HEV 是负责 LN 和 TLS 中幼稚 T 细胞募集和教育的特殊脉管系统。在这里，携带可调节 ETV2 等位基因的人类多能干细胞的正交诱导分化用于快速有效地诱导内皮分化。胚状体的组装结合了原始诱导型内皮细胞和原代人 LN 成纤维细胞网状细胞，形成 HEV 样结构，这些结构可以聚集成 3D 类器官（HEVO）。移植到免疫缺陷小鼠体内后，HEVO 成功移植并形成淋巴结构，募集抗原呈递细胞和过继转移的淋巴细胞，因此表现出基本的 TLS 能力。结果进一步表明，在功能上，HEVOs 可以通过过继转移的 T 淋巴细胞组织免疫反应并促进抗肿瘤活性。总的来说，这些实验方法代表了一种创新且可扩展的概念验证策略，用于制造生物工程 TLS，该 TLS 可以在体内部署以增强适应性免疫反应。

"点击查看英文标题和摘要"

Rapid Generation of hPSC-Derived High Endothelial Venule Organoids with In Vivo Ectopic Lymphoid Tissue Capabilities

Bioengineering strategies for the fabrication of implantable lymphoid structures mimicking lymph nodes (LNs) and tertiary lymphoid structures (TLS) could amplify the adaptive immune response for therapeutic applications such as cancer immunotherapy. No method to date has resulted in the consistent formation of high endothelial venules (HEVs), which is the specialized vasculature responsible for naïve T cell recruitment and education in both LNs and TLS. Here orthogonal induced differentiation of human pluripotent stem cells carrying a regulatable ETV2 allele is used to rapidly and efficiently induce endothelial differentiation. Assembly of embryoid bodies combining primitive inducible endothelial cells and primary human LN fibroblastic reticular cells results in the formation of HEV-like structures that can aggregate into 3D organoids (HEVOs). Upon transplantation into immunodeficient mice, HEVOs successfully engraft and form lymphatic structures that recruit both antigen-presenting cells and adoptively-transferred lymphocytes, therefore displaying basic TLS capabilities. The results further show that functionally, HEVOs can organize an immune response and promote anti-tumor activity by adoptively-transferred T lymphocytes. Collectively, the experimental approaches represent an innovative and scalable proof-of-concept strategy for the fabrication of bioengineered TLS that can be deployed in vivo to enhance adaptive immune responses.

更新日期：2024-02-02

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