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工程人类多能干细胞系,以逃避异种移植障碍

Hannah A Pizzato¹, Paula Alonso-Guallart², James Woods²

¹Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ, USA.

bioRxiv : the preprint server for biology

|July 10, 2023

概括

为了防止移植干细胞的排斥,研究人员将人类多能干细胞 (hPSCs) 基因改造,以逃避免疫反应. 这项研究确定了T细胞,NK细胞和补充逃避对于成功移植在小鼠中至关重要.

科学领域:

免疫学免疫学免疫学
再生医学是一种再生医学.
干细胞生物学干细胞生物学

背景情况:

同源性人类多能干细胞 (hPSC) 衍生细胞面临免疫性排斥,阻碍治疗性移植.
在免疫能力强的模型中进行临床前测试需要为免疫规避而设计的hPSC.

研究的目的:

为了确定hPSC移植的免疫障碍.
为免疫规避设计hPSC,以便在免疫能力强的小鼠中进行临床前测试.

主要方法:

基因的基因切除 (例如*β2m*, *Tap1*, *Ciita*) 以减少hPSC中的HLA-I,HLA-II和NK细胞连接体的表达.
工程 hPSCs 来表达免疫抑制因子 (Qa1,H2-K^b,CD55,Cry,CD59,CD24,CD47,PD-L1) 的原因.
在免疫缺陷和免疫能力较强的野生类型小鼠中进行瘤形成测定.

主要成果:

转基因hPSCs和未经编辑的hPSCs在免疫缺陷小鼠中形成了瘤,但在免疫能力强小鼠中被拒绝.
表达Qa1,H2-K^b,CD55,Crry和CD59的hPSCs在野生型小鼠中表现出持久性瘤.
其他因素 (CD24,CD47,PD-L1) 并没有显著影响瘤的持续性;补充剂和NK细胞缺乏也促进了持续性.

结论:

为了防止hPSC衍生细胞的免疫排斥,T细胞,NK细胞和补充逃避是必不可少的.
工程化hPSC及其后代可用于提炼组织特异性免疫屏障.
开发的hPSCs适合在免疫能力强的小鼠模型中进行临床前测试.

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