Ribosome biogenesis controls cranial suture MSC fate via the complement pathway in mouse and human iPSC models.
Ribosome biogenesis controls cranial suture MSC fate via the complement pathway in mouse and human iPSC models.
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DOI：
10.1016/j.stemcr.2023.10.015
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发表时间：
2023-12-12
影响因子：
5.9
通讯作者：
Chen, Jian-Fu
中科院分区：
文献类型：
--
作者：
Jariyasakulroj, Supawadee;Zhang, Wei;Bai, Jianhui;Zhang, Minjie;Lu, Zhipeng;Chen, Jian-Fu
整体核糖体生物合成的破坏选择性地影响颅面组织，其机制尚不清楚。颅缝早闭症是一种先天性颅面疾病，其特征在于颅缝过早融合伴缝间充质干细胞（MSC）丢失。在这里，我们专注于核糖体病疾病基因Snord118，它编码一个小核仁RNA（snoRNA），在遗传上干扰核糖体生物合成在缝合骨髓间充质干细胞使用小鼠和人类诱导多能干细胞（iPSC）模型。Snord118耗竭表现出p53激活，细胞死亡增加，增殖减少，和过早的成骨分化的MSC，导致缝生长和颅缝早闭缺陷。从机制上讲，Snord118缺陷导致核糖体蛋白的翻译失调和补体途径基因的下调。通过敲除补体C3a受体1（C3ar1）进一步破坏补体途径加剧了突变小鼠中的MSC和缝合缺陷，而激活补体途径则挽救了MSC细胞命运和缝合生长缺陷。因此，核糖体生物合成通过补体途径控制MSC的命运，以防止颅缝早闭。核糖体病基因Snord118在小鼠缝间充质干细胞中的缺失导致颅缝早闭人类iPSC模型揭示了核糖体生物发生介导的对MSC命运的调节核糖体生物发生选择性地调节补体途径补体途径控制MSC细胞命运用于颅缝生长Chen和同事开发了新的小鼠和人类iPSC模型用于核糖体病基因Snord118突变。他们发现，全球核糖体生物合成的破坏选择性地调节补体途径，并导致颅缝间充质干细胞（MSC）的细胞命运改变，最终导致颅缝早闭样缺陷。
Disruption of global ribosome biogenesis selectively affects craniofacial tissues with unclear mechanisms. Craniosynostosis is a congenital craniofacial disorder characterized by premature fusion of cranial suture(s) with loss of suture mesenchymal stem cells (MSCs). Here we focused on ribosomopathy disease gene Snord118, which encodes a small nucleolar RNA (snoRNA), to genetically disturb ribosome biogenesis in suture MSCs using mouse and human induced pluripotent stem cell (iPSC) models. Snord118 depletion exhibited p53 activation, increased cell death, reduced proliferation, and premature osteogenic differentiation of MSCs, leading to suture growth and craniosynostosis defects. Mechanistically, Snord118 deficiency causes translational dysregulation of ribosomal proteins and downregulation of complement pathway genes. Further complement pathway disruption by knockout of complement C3a receptor 1 (C3ar1) exacerbated MSC and suture defects in mutant mice, whereas activating the complement pathway rescued MSC cell fate and suture growth defects. Thus, ribosome biogenesis controls MSC fate via the complement pathway to prevent craniosynostosis. Ribosomopathy gene Snord118 deletion in mouse suture MSCs causes craniosynostosis A human iPSC model reveals the ribosome biogenesis-mediated regulation of MSC fate Ribosome biogenesis selectively regulates the complement pathway The complement pathway controls MSC cell fate for cranial suture growth Chen and colleagues developed new mouse and human iPSC models for ribosomopathy disease gene Snord118 mutations. They found that a disruption of global ribosome biogenesis selectively regulates the complement pathway and leads to the cell fate changes of cranial suture mesenchymal stem cells (MSCs), which ultimately causes craniosynostosis-like defects.
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4.5
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