Absence of the primary cilia formation gene Talpid3 impairs muscle stem cell function.
Absence of the primary cilia formation gene Talpid3 impairs muscle stem cell function.
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DOI：
10.1038/s42003-023-05503-9
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发表时间：
2023-11-04
影响因子：
5.9
通讯作者：
Munsterberg, Andrea
中科院分区：
文献类型：
--
作者：
Martinez-Heredia, Victor;Blackwell, Danielle;Sebastian, Sujith;Pearson, Timothy;Mok, Gi Fay;Mincarelli, Laura;Utting, Charlotte;Folkes, Leighton;Poeschl, Ernst;Macaulay, Iain;Mayer, Ulrike;Munsterberg, Andrea
骨骼肌干细胞（MuSC）对于损伤后的组织稳态和修复至关重要。在激活后，它们增殖以产生分化的成肌细胞。一部分细胞自我更新，重新进入肌纤维外基底层下的MuSC龛并进入静止状态。静止的MuSC具有初级纤毛，其在细胞周期进入时被分解。离体实验表明纤毛对于MuSC自我更新是重要的，然而，它们对体内肌肉再生的要求仍然知之甚少。Talpid 3（TA 3）是初级纤毛形成和Hedgehog（Hh）信号传导所必需的。在这里，我们使用他莫昔芬诱导的条件性删除TA 3的MuSC（iSC-KO），并显示再生受损的细胞毒性损伤。再生后MuSC的耗尽表明自我更新受损，也与重复损伤后TA 3 iSC-KO小鼠中的加重表型一致。从肌纤维分离的MuSC后代的单细胞转录组学鉴定了几种信号传导途径的组分，其在不存在TA 3的情况下被失调，包括Hh和Wnt。Wnt的药理学激活恢复肌肉再生，而Purmorphamine，一种Hh途径中Smoothened（Smo）辅助受体的激活剂，没有作用。总之，我们的数据表明，TA 3和初级纤毛对MuSC自我更新很重要，药物治疗可以有效地恢复肌肉再生。Talpid 3基因是初级纤毛形成所必需的，是骨骼肌干细胞（MuSC）自我更新所必需的，并且MuSC中Talpid 3的缺失会使hedgehog和Wnt信号通路失调。
Skeletal muscle stem cells (MuSC) are crucial for tissue homoeostasis and repair after injury. Following activation, they proliferate to generate differentiating myoblasts. A proportion of cells self-renew, re-enter the MuSC niche under the basal lamina outside the myofiber and become quiescent. Quiescent MuSC have a primary cilium, which is disassembled upon cell cycle entry. Ex vivo experiments suggest cilia are important for MuSC self-renewal, however, their requirement for muscle regeneration in vivo remains poorly understood. Talpid3 (TA3) is essential for primary cilia formation and Hedgehog (Hh) signalling. Here we use tamoxifen-inducible conditional deletion of TA3 in MuSC (iSC-KO) and show that regeneration is impaired in response to cytotoxic injury. Depletion of MuSC after regeneration suggests impaired self-renewal, also consistent with an exacerbated phenotype in TA3iSC-KO mice after repeat injury. Single cell transcriptomics of MuSC progeny isolated from myofibers identifies components of several signalling pathways, which are deregulated in absence of TA3, including Hh and Wnt. Pharmacological activation of Wnt restores muscle regeneration, while purmorphamine, an activator of the Smoothened (Smo) co-receptor in the Hh pathway, has no effect. Together, our data show that TA3 and primary cilia are important for MuSC self-renewal and pharmacological treatment can efficiently restore muscle regeneration. The Talpid3 gene, essential for primary cilia formation, is required for skeletal muscle stem cell (MuSC) self-renewal and loss of Talpid3 in MuSCs deregulates hedgehog and Wnt signalling pathways.
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DOI：
10.1073/pnas.1323265111
发表时间：
2014-06-24
影响因子：
11.1
作者：
Fu, Wenxiang;Asp, Patrik;Dynlacht, Brian David
通讯作者：
Dynlacht, Brian David
影响因子：
2.7
作者：
Abu-Elmagd, Muhammad;Robson, Lesley;Munsterberg, Andrea
通讯作者：
Munsterberg, Andrea
影响因子：
4.6
作者：
Anderson, Claire;Thorsteinsdottir, Solveig;Borycki, Anne-Gaelle
通讯作者：
Borycki, Anne-Gaelle
影响因子：
--
作者：
Fan, Chih-Wei;Chen, Baozhi;Lum, Lawrence
通讯作者：
Lum, Lawrence
影响因子：
4.6
作者：
Borday, Caroline;Cabochette, Pauline;Perron, Muriel
通讯作者：
Perron, Muriel