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人类原生T细胞的分化由胸腺模拟细胞外基质的机械阻力调节

Nicholas Jeffreys, Kyle T Ruark, Joshua M Price

bioRxiv : the preprint server for biology

|September 5, 2025

概括

通过增强Notch1信号传递,使用软粘性水凝的工程胸膜 (ETN) 促进T细胞的发育. 较硬的基质抑制T细胞系的结合,有利于骨髓细胞的分化.

科学领域:

生物技术
发育生物学
生物材料科学

背景情况:

治疗T细胞工程依赖于使用工程化胸膜 (ETN) 模仿胸膜.
像Notch1-DLL-4和α4β1-整合素-VCAM-1这样的关键相互作用是机械敏感的,但它们在ETN设计中的作用被忽视了.
了解机械传导对于控制T细胞发育至关重要.

研究的目的:

研究机械力量在血造干细胞 (HSC) 调节T细胞发育中的作用.
为研究T细胞分化开发具有可调节的机械性质的3D工程 (ETN).
在对矩阵力学反应中阐明Notch1和整合素信号之间的分子合作性.

主要方法:

使用DLL-4和VCAM-1作为3DETN模型的互穿网络 (IPN) 水凝 (原型I和酸盐).
正向控制的机械特征:刚性,粘弹性和连接体密度.
在3DETN中培养出由带血衍生的CD34+HSC,以评估T细胞前代的分化.

主要成果:

软粘性基质增强了Notch1通路的激活和NICD核导入,维持T细胞的发育.
刚性,弹性矩阵抑制了HSC与T系的结合,并促进了骨髓分化.
在信号通路中证明了机械互惠性,这对胸膜形成至关重要.

结论:

在T细胞发育过程中,细胞外基因机制是控制HSC命运决定的关键变量.
胸膜微环境的粘弹性特性显著影响T细胞谱系的承诺.
这项研究为设计利用机械传导改善T细胞治疗的先进ETN提供了基础.

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