Feng Tengfei, Xu Qi, Wang Shuangshuang, Hou Dongyu, Wu Xunwei
Savaid Stomatology School, Hangzhou Medical College, Hangzhou, Zhejiang, 311399, China.
Ningbo Stomatology Hospital, Ningbo, Zhejiang, 315000, China.
Biochem Biophys Rep. 2025 May 27;43:102065. doi: 10.1016/j.bbrep.2025.102065. eCollection 2025 Sep.
Tunneling nanotubes (TNTs) are membranous structures that enable direct intercellular transfer of mitochondria, proteins, RNAs, and signaling molecules, playing key roles in tissue repair, immune coordination, and stress adaptation. Among their critical functions, TNT-mediated mitochondrial transfer rescues metabolically impaired cells, yet the regulatory mechanisms governing TNT formation and function remain incompletely understood. Recent studies highlight the Wnt signaling pathway-a conserved regulator of cell fate, polarity, and cytoskeletal remodeling-as a central modulator of TNT dynamics. Through its canonical (Wnt/β-catenin) and non-canonical (Wnt/PCP and Wnt/Ca) branches, Wnt signaling orchestrates actin filament organization, bundling, and turnover, all of which are essential for TNT biogenesis and stability. This review critically examines the mechanistic intersection between Wnt signaling and TNTs, with an emphasis on how Wnt-driven cytoskeletal remodeling supports intercellular connectivity. Beyond basic mechanistic insights, we also explore the physiological and pathological relevance of this crosstalk-including its roles in tissue regeneration, immune modulation, cancer progression, and neurodegeneration. While the Wnt-TNT axis offers therapeutic promise, its context-dependent effects demand careful consideration.
隧道纳米管（TNTs）是一种膜性结构，能够实现线粒体、蛋白质、RNA和信号分子的直接细胞间转移，在组织修复、免疫协调和应激适应中发挥关键作用。在其关键功能中，TNT介导的线粒体转移可挽救代谢受损的细胞，然而，TNT形成和功能的调控机制仍未完全明确。最近的研究强调了Wnt信号通路——一种保守的细胞命运、极性和细胞骨架重塑调节因子——作为TNT动态变化的核心调节因子。通过其经典（Wnt/β-连环蛋白）和非经典（Wnt/平面细胞极性蛋白和Wnt/钙）分支，Wnt信号通路协调肌动蛋白丝的组织、捆绑和周转，所有这些对于TNT的生物发生和稳定性都是必不可少的。这篇综述批判性地研究了Wnt信号通路与TNTs之间的机制交叉点，重点关注Wnt驱动的细胞骨架重塑如何支持细胞间连接。除了基本的机制见解外，我们还探讨了这种相互作用的生理和病理相关性，包括其在组织再生、免疫调节、癌症进展和神经退行性变中的作用。虽然Wnt-TNT轴具有治疗前景，但其依赖于背景的效应需要仔细考虑。
