白血病干细胞源性外泌体靶向递送miRNA-21在人参皂苷Rg1介导白血病干细胞衰老中的作用机制

Leukemia stem cells (LSCs) have the crucial role in leukemia initiation and progression, a new treatment research strategy is to find a natural drug that can target kill LSCs while protecting the normal hematopoietic function. Our earlier studies show that ginsenoside Rg1 has bidirectional effects of hematopoietic stem and progenitor cells ageing alleviation and K562 cells ageing promotion. Based on this encouraging result, we hypothesize that Rg1 can induce LSCs senescence and reduce the stemness of LSCs. The latest study indicated that exosomal miRNA-21 promotes the proliferation and differentiation of leukemia cells through targeting PTEN/PI3K/Akt signaling pathway. But how the exosomal miRNA-21 promotes the stemness of LSCs and the effect of Rg1 in it is so far unclear. In this study, by targetting at LSCs, we apply the latest stem cell research techniques to investigate the effect of exosomal miRNA-21 mediated PTEN/PI3K/Akt signaling pathway in the stemness maintenance of LSCs induced by ginsenoside Rg1 in vitro and in vivo. The result can elucidate the effect and mechanism of Rg1 to cure leukemia through inducing LSCs senescence and reducing the stemness of LSCs. The study aims to provide the evidence for development mechanism of leukemia in stem cell level and to provide a new approach in clinical leukemia therapy.

白血病干细胞（LSCs）在白血病发生发展中起决定作用，寻找能靶向清除LSCs，又能保护正常造血功能的中药诱导剂成为治疗白血病研究的新策略。我们前期研究证明人参皂苷Rg1具有延缓造血干/祖细胞衰老和促进K562白血病细胞衰老的双向调控作用，据此我们推测Rg1可能靶向诱导LSCs衰老，下调LSCs干性。最新研究报道外泌体通过递送miRNA-21靶向调控PTEN/PI3K/Akt通路促进白血病细胞增殖分化。外泌体递送miRNA-21在LSCs干性维持中的作用及Rg1的调控机制尚不明确。本研究以LSCs为作用靶点，采用干细胞最新研究技术，从体内外两条途径探讨外泌体递送miRNA-21在LSCs干性维持中的作用及Rg1靶向干预机制，课题将阐释人参“补气祛邪”调控LSCs衰老，下调LSCs干性以治疗白血病的作用机理，为从干细胞层面研究白血病发生发展机制提供实验依据，为临床防治白血病提供新思路和新方法。

白血病干细胞（LSCs）在白血病发生发展中起决定作用，寻找能靶向清除LSCs，又能保护正常造血功能的中药诱导剂成为治疗白血病研究的新策略。我们前期研究证明人参皂苷Rg1具有延缓造血干/祖细胞衰老和促进K562白血病细胞衰老的双向调控作用，据此我们推测Rg1可能靶向诱导LSCs衰老，下调LSCs干性。最新研究报道外泌体通过递送miRNA-21靶向调控PTEN/PI3K/Akt通路促进白血病细胞增殖分化。外泌体递送miRNA-21在LSCs干性维持中的作用及Rg1的调控机制尚不明确。本研究以LSCs为作用靶点，从体内和体外两条途径探讨外泌体递送miRNA-21在LSCs干性维持中的作用及Rg1靶向干预机制，结果证实exosome投递miR-21靶向调控PTEN/PI3K/Akt信号通路是人参皂苷Rg1下调LSCs干性，诱导LSCs衰老的作用机制，阐述了人参“补气祛邪”调控LSCs衰老，下调LSCs干性以治疗白血病的作用机理，为从干细胞层面研究白血病发生发展机制提供实验依据；我们前期的研究结果证实人参皂苷Rg1能有效延缓HSC/HPC衰老，Rg1通过调控SIRT1-mTOR通路诱导LSCs衰老；本课题研究结果结合前期研究结果，阐释了人参皂苷Rg1 在造血系统中的“扶正驱邪”双重调控作用，即正向调控HSC/HPC潜能，负向诱导LSCs衰老，为临床治疗白血病提供新思路和新方法。