由Bnip3lb驱动的髓会维持胚胎造血干细胞池的扩张
bioRxiv : the preprint server for biology
|October 10, 2024
概括
胚胎造血干细胞 (HSPC) 通过mitophagy维持多能性,这是一种调节活性氧物种 (ROS) 的过程. 激活髓细胞增强HSPC功能和潜力,为干细胞疗法提供新的途径.
科学领域:
- 发展生物学 发展生物学
- 干细胞生物学 干细胞生物学
- 细胞的新陈代谢
背景情况:
- 胚胎造血干细胞和原始细胞 (HSPCs) 具有独特的增殖和多能能力,对发育至关重要,在体外复制很难.
- 了解管理胚胎HSPC维护的监管机制对于推进再生医学和基于细胞的疗法至关重要.
研究的目的:
- 阐明反应性氧物种 (ROS) 和线粒菌在胚胎HSPC增殖和多能性的调节中的作用.
- 调查胚胎HSPCs中Bnip3lb相关线粒的特定机制及其对造血干细胞发育的影响.
- 探索诱导人类诱导的多能干细胞 (hiPSC) 衍生的造血细胞原始体中诱导线粒细胞的治疗潜力.
主要方法:
- 使用斑马鱼模型 (Tg(ubi:mitoQC)) 进行活体成像和scRNAseq来追踪HSPC发育和线粒细胞衰变.
- 采用Bnip3lb的淘汰和抗氧化剂的暴露,以评估线粒和ROS在HSPC维护中的作用.
- 研究了线粒细胞诱导对胚胎HSPC和淋巴细胞原始体数量的影响.
- 通过连续复制试验,评估了在线细胞激活后的hiPSC衍生的造血原体的功能能力.
主要成果:
- 胚胎的HSPCs通过Bnip3lb关联的线粒细胞衰变来调节ROS水平,这是在内皮细胞转化为造血细胞的过程中以及尾部造血细胞组织 (CHT) 的殖民化过程中.
- Knockdown of Bnip3lb 损害了线粒,导致CHT 中的HSPC 数量减少,骨髓偏差分化增加,以及亡,这些效应被抗氧化剂所挽救.
- 相反,增强的线粒细胞吸收增加了胚胎HSPC和淋巴细胞原始体种群.
- 线细胞激活显著改善了hiPSC衍生的造血原体的ex vivo功能能力和串行复制潜力.
结论:
- ROS对于最初的HSPC形成至关重要,但对其随后的维护有害.
- Bnip3lb导向的线粒是控制二级内的HSPC中ROS水平的关键机制.
- 线性保护新生的HSPCs免受ROS诱导的亡,并保持它们的多效.
- 诱导线粒是一种有希望的策略,可以增强iPSC衍生HSPCs的长期造血潜力,用于治疗应用.
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