Signaling modality within gp130 receptor enhances tissue regeneration (Canine scRNA-seq)

Adult mammals are incapable of multi-tissue regeneration and augmentation of this potential may drastically shift current therapeutic paradigms. Here, we found that a common co-receptor of IL-6 cytokines, glycoprotein 130 (gp130), serves as a major nexus integrating various context-specific signaling inputs to either promote regenerative outcomes or aggravate disease progression. Via genetic and pharmacological experiments in vitro and in vivo, we demonstrated that a signaling tyrosine 814 (Y814) within gp130 serves as a major cellular stress sensor. Mice with constitutively inactivated Y814 (F814) exhibit regenerative, not reparative, responses after wounding in skin and anti-degenerative responses in the synovial joint. In addition, pharmacological inhibition of gp130 Y814 results in regeneration of multiple tissues in several species as well as disease modification in animal models of osteoarthritis. Our study characterizes a novel molecular mechanism that, if selectively manipulated, enhances the intrinsic regenerative capacity while preventing pathological outcomes in injury and disease. Overall design: Single-cell mRNA sequencing for dog synovium treated with or without R805 using 10x Genomics.

成年哺乳动物无法实现多组织再生，若能增强该再生潜能，或将彻底改变当前的治疗范式。本研究发现，IL-6细胞因子家族的共同共受体——糖蛋白130（glycoprotein 130，gp130）——可作为核心枢纽，整合多种情境特异性的信号输入，进而调控再生结局的产生或疾病进程的加重。通过体外及体内的遗传学与药理学实验，本研究证实gp130胞内的信号转导位点酪氨酸814（tyrosine 814，Y814）可作为主要的细胞应激感受器。携带组成型失活Y814（即F814突变）的小鼠，在皮肤创伤后可产生再生而非修复性应答，并在滑膜关节中展现出抗退行性病变的效应。此外，对gp130 Y814进行药理学抑制，可在多个物种中实现多组织再生，并在骨关节炎动物模型中实现疾病修饰。本研究阐明了一种全新的分子机制：若对该机制进行选择性干预，可增强机体的固有再生能力，同时避免损伤与疾病引发的病理性结局。实验整体设计：采用10x Genomics技术，对经R805处理与未经R805处理的犬滑膜组织进行单细胞mRNA测序。