合成生物学 ›› 2022, Vol. 3 ›› Issue (6): 1109-1125.DOI: 10.12211/2096-8280.2022-029
郭伟, 付禹豪, 范盈盈, 周佳铃, 李鑫, 魏平
收稿日期:
2022-05-23
修回日期:
2022-09-05
出版日期:
2022-12-31
发布日期:
2023-01-17
通讯作者:
魏平
作者简介:
基金资助:
Wei GUO, Yuhao FU, Yingying FAN, Jialing ZHOU, Xin LI, Ping WEI
Received:
2022-05-23
Revised:
2022-09-05
Online:
2022-12-31
Published:
2023-01-17
Contact:
Ping WEI
摘要:
哺乳动物细胞的趋化与迁移对于生命过程重要。许多关键生理过程依赖于细胞迁移,从胚胎发育到骨和血管生成,细胞迁移在组织修复、炎症、免疫应答和癌症转移中起关键作用。在人体内,细胞必须能够感知所在环境中的各种线索,并趋向或远离这些线索,以便在发育过程中执行形态发生程序,面对病原体产生免疫以及修复受损组织。这些过程的失控会给生命带来严重的不良后果,细胞如果不能以适当的方式进行迁移,就会导致发育和免疫的缺陷、慢性伤口的无法愈合以及癌症侵袭性转移、自身免疫和纤维化等疾病。细胞迁移的机制是通过表面受体和机械感知分子将环境中的化学、物理线索传递给细胞内信号网络,通过在细胞内建立不对称的分子空间梯度,激活下游细胞骨架调控因子使细胞发生持续的极化现象。整个过程涉到将线索传递到胞内的膜受体、胞内第二信使、细胞骨架调节因子、肌动蛋白组装等一系列组分和步骤。因此系统性理解细胞趋化过程对于发展哺乳动物细胞合成生物学理性设计与改造能力具有重要意义。工程化改造细胞趋化迁移能力来实现对细胞迁移的人工控制,将是哺乳动物细胞工程的重要方向。这能帮助人们进一步探索发育机制,提升免疫治疗效果,治愈由细胞趋化紊乱造成的疾病,加快组织损伤的修复。本综述将从细胞趋化的迁移方式、环境线索、分子机制、工程改造、临床应用几个方面对哺乳动物细胞的趋化迁移进行综述介绍。
中图分类号:
郭伟, 付禹豪, 范盈盈, 周佳铃, 李鑫, 魏平. 哺乳动物细胞的趋化迁移及人工控制[J]. 合成生物学, 2022, 3(6): 1109-1125.
Wei GUO, Yuhao FU, Yingying FAN, Jialing ZHOU, Xin LI, Ping WEI. Artificial control of mammalian cell chemotaxis and motility[J]. Synthetic Biology Journal, 2022, 3(6): 1109-1125.
图2 细胞趋化迁移机制(a)细胞的两种主要迁移模式(间充质迁移,变形虫迁移)及其转换;(b)细胞迁移环境(化学线索趋化、趋触,物理线索的硬度、拓扑结构、电场);(c)细胞迁移分子调控网络(外部线索感知,兴奋信号转导,肌动蛋白组装)
Fig. 2 Cellular chemotactic mechanisms
图3 细胞趋化迁移的工程化调控(a)利用化学小分子对细胞趋化迁移进行调控,仅由合成配体激活的受体(RASSL)能响应正交小分子如氯氮平-N-氧化物(clozapine-N-oxide,CNO)诱导迁移,化学诱导二聚化(CID)是一种灵活的方法,可招募蛋白质到细胞的特定位置。(b)利用光刺激调控细胞迁移,PA-CXCR4在505 nm光响应下传输细胞内CXCR信号,PA-CXCR4的局部激活可诱导T细胞极化和定向迁移。PA-Rac1利用蓝光诱导蛋白二聚化,实现Rac1膜定位介导细胞迁移。BcLOV4利用动态膜结合蛋白与GTPase融合,实现单个蛋白的光控诱导迁移系统。(c)利用磁场对细胞迁移进行调控, TF-CaRQ利用嵌合瞬时受体电位香草素1 (TRPV1)和嵌合RhoA蛋白,通过磁控引起Ca2+内流,Ca2+激活RhoA,从而允许磁场开启细胞迁移, MNP-GTPase通过将GTPase与磁纳米颗粒融合,在磁场作用下改变GTPase膜定位诱导迁移
Fig. 3 Engineering regulation of cell chemotaxis
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