Unraveling radiation-induced skeletal muscle damage: Insights from a 3D human skeletal muscle organoid model

IF 4.6 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Biochimica et biophysica acta. Molecular cell research Pub Date : 2024-06-25 DOI:10.1016/j.bbamcr.2024.119792
Yifei Jiang , Runtao Zhou , Fawei Liao , Ganggang Kong , Jingguang Zeng , Yixun Wu , Xubo Li , Bo Wang , Fangze Qi , Shiju Chen , Qintang Zhu , Liqiang Gu , Canbin Zheng
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Abstract

Background

Three-dimensional (3D) organoids derived from human pluripotent stem cells (hPSCs) have revolutionized in vitro tissue modeling, offering a unique opportunity to replicate physiological tissue organization and functionality. This study investigates the impact of radiation on skeletal muscle response using an innovative in vitro human 3D skeletal muscle organoids (hSMOs) model derived from hPSCs.

Methods

The hSMOs model was established through a differentiation protocol faithfully recapitulating embryonic myogenesis and maturation via paraxial mesodermal differentiation of hPSCs. Key skeletal muscle characteristics were confirmed using immunofluorescent staining and RT-qPCR. Subsequently, the hSMOs were exposed to a clinically relevant dose of 2 Gy of radiation, and their response was analyzed using immunofluorescent staining and RNA-seq.

Results

The hSMO model faithfully recapitulated embryonic myogenesis and maturation, maintaining key skeletal muscle characteristics. Following exposure to 2 Gy of radiation, histopathological analysis revealed deficits in hSMOs expansion, differentiation, and repair response across various cell types at early (30 min) and intermediate (18 h) time points post-radiation. Immunofluorescent staining targeting γH2AX and 53BP1 demonstrated elevated levels of foci per cell, particularly in PAX7+ cells, during early and intermediate time points, with a distinct kinetic pattern showing a decrease at 72 h. RNA-seq data provided comprehensive insights into the DNA damage response within the hSMOs.

Conclusions

Our findings highlight deficits in expansion, differentiation, and repair response in hSMOs following radiation exposure, enhancing our understanding of radiation effects on skeletal muscle and contributing to strategies for mitigating radiation-induced damage in this context.

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揭示辐射诱导的骨骼肌损伤:三维人体骨骼肌类器官模型的启示
背景:由人类多能干细胞(hPSCs)衍生的三维(3D)器官组织彻底改变了体外组织建模,为复制生理组织结构和功能提供了独特的机会。本研究利用源自hPSCs的创新体外人三维骨骼肌器官组织(hSMOs)模型,研究辐射对骨骼肌反应的影响:hSMOs模型是通过hPSCs副中胚层分化忠实再现胚胎肌发生和成熟的分化方案建立的。通过免疫荧光染色和 RT-qPCR 确认了骨骼肌的主要特征。随后,将 hSMOs 暴露于临床相关剂量的 2 Gy 辐射,并使用免疫荧光染色和 RNA-seq 分析其反应:结果:hSMO模型忠实地再现了胚胎肌的发生和成熟,保持了骨骼肌的关键特征。暴露于 2 Gy 辐射后,组织病理学分析表明,在辐射后早期(30 分钟)和中期(18 小时),各种细胞类型的 hSMOs 扩增、分化和修复反应均出现缺陷。针对γH2AX和53BP1的免疫荧光染色显示,在早期和中期时间点,每个细胞中的病灶水平升高,尤其是在PAX7+细胞中,其明显的动力学模式显示在72小时后下降。RNA-seq数据全面揭示了hSMOs内的DNA损伤反应:我们的研究结果突显了辐照后 hSMOs 在扩增、分化和修复反应方面的缺陷,加深了我们对辐射对骨骼肌影响的理解,并有助于在这种情况下制定减轻辐射所致损伤的策略。
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来源期刊
CiteScore
10.00
自引率
2.00%
发文量
151
审稿时长
44 days
期刊介绍: BBA Molecular Cell Research focuses on understanding the mechanisms of cellular processes at the molecular level. These include aspects of cellular signaling, signal transduction, cell cycle, apoptosis, intracellular trafficking, secretory and endocytic pathways, biogenesis of cell organelles, cytoskeletal structures, cellular interactions, cell/tissue differentiation and cellular enzymology. Also included are studies at the interface between Cell Biology and Biophysics which apply for example novel imaging methods for characterizing cellular processes.
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