抑制I型PRMTs改革肌肉干细胞身份,增强它们的治疗能力
Claudia Dominici1,2, Oscar D Villarreal1, Junio Dort3
1Segal Cancer Center, Lady Davis Institute for Medical Research, McGill University, Montreal, Canada.
eLife
|June 7, 2023
概括
使用MS023抑制I型蛋白质氨酸甲基转移酶 (PRMTs) 增强了肌肉干细胞 (MuSC) 的增殖和自我更新. 这在疾病模型中改善了肌肉再生和力量.
科学领域:
- 肌肉干细胞生物学 肌肉干细胞生物学
- 再生医学是一种再生医学.
- 分子药理学分子药理学
背景情况:
- 肌肉干细胞 (MuSCs) 对于骨肌肉再生至关重要.
- 针对肌肉疾病的治疗策略旨在增强肌肉功能.
- 在保持干度的同时,MuSCs的活体扩张是一个重大挑战.
研究的目的:
- 研究I型蛋白质氨酸甲基转移酶 (PRMTs) 抑制对MuSC扩张和功能的影响.
- 在PRMT抑制后探索MuSCs中的分子和代谢变化.
- 在肌肉再生和疾病模型中评估PRMT抑制的MuSCs的治疗潜力.
主要方法:
- 用PRMT抑制剂MS023培养的MuSCs的活体培养.
- 单细胞RNA测序 (scRNAseq) 用于分析细胞群和基因表达.
- 对 MuSC 干性标记物 (Pax7) 和静止的评估.
- 代谢分析,包括糖解和氧化酸化 (OxPhos).
- 在体内移植试验和肌肉再生研究.
- 在Duchenne肌肉发育不良症的临床前小鼠模型中的评估.
主要成果:
- MS023治疗显著增加了ex vivo培养的MuSCs的繁殖能力.
- scRNAseq揭示了具有高Pax7表达和静止标记的亚群,表明增强的自我更新.
- 用MS023治疗的MuSCs表现出细胞代谢的改变,包括高调的糖解和OxPhos.
- 移植的 MuSCs 证明了改进的移植和有效的肌肉再生.
- MS023治疗改善了杜氏肌肉衰竭小鼠模型中的握力.
结论:
- 使用MS023抑制I型PRMTs促进了MuSC的扩散和自我更新.
- 改变的细胞代谢伴随着治疗的MuSCs的增强的茎状特性.
- 抑制PRMT是一种有前途的策略,可以改善基于MuSC的肌肉再生和疾病治疗方法.
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