Busulfan Suppresses Autophagy in Mouse Spermatogonial Progenitor Cells via mTOR of AKT and p53 Signaling Pathways
Busulfan Suppresses Autophagy in Mouse Spermatogonial Progenitor Cells via mTOR of AKT and p53 Signaling Pathways
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白消安通过 AKT 和 p53 信号通路的 mTOR 抑制小鼠精原祖细胞的自噬
DOI：
10.1007/s12015-020-10027-4
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发表时间：
2020-08-24
影响因子：
4.8
通讯作者：
Zou, Kang
中科院分区：
文献类型：
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作者：
Wei, Rui;Zhang, Xiaoyu;Zou, Kang
精原祖细胞（spermatogonial progenitor cells，SPC）是睾丸中一类罕见的未分化生殖细胞，具有再生能力，支持精子发生。白消安作为一种广泛应用于肿瘤治疗或骨髓移植的药物，对SPC群体有严重的副作用，并导致不育。近年来，越来越多的证据表明自噬在外源性应激下干细胞的维持中起保护作用。为了更好地了解自噬在SPC命运中的作用，我们研究了白消安应激下SPC中自噬的潜在功能，发现白消安处理诱导小鼠SPC中自噬囊泡和自噬体的形成。随后，自噬和SPC维持和存活的连接以剂量依赖性方式被证明。此外，mTOR被鉴定为SPC中自噬的必需因子，其机制复杂：（1）在短期白消安处理期间，mTOR被AKT磷酸化以激活其靶基因p70s6激酶，导致自噬抑制。(2)mTOR与p53共同介导自噬，调节SPC的命运。总的来说，本研究的观察结果表明，中度自噬有效地保护SPC免受化疗的应激，这可能为临床生育保护提供重要提示。
In testis, a rare undifferentiated germ cell population with the capacity to regenerate robustly and support spermatogenesis, is defined as spermatogonial progenitor cells (SPCs) population. As a widely used drug for tumor therapy or bone marrow transplantation, busulfan has a severe side effect on SPCs population and causes a consequent infertility. Recently, accumulating evidence revealed the protective role of autophagy in stem cell maintenance under exogenous stress. To better understand the role of autophagy in SPCs fates, we investigated the potential function of autophagy in SPCs under busulfan stress, and found that treatment of busulfan induced the formation of autophagic vesicles and autophagosomes in mouse SPCs. Subsequently, a connection of autophagy and SPCs maintenance and survival was demonstrated in a dose-dependent manner. Moreover, mTOR was identified as an essential factor for autophagy in SPCs with a complicated mechanism: (1) mTOR is phosphorylated by AKT to activate its target genes, p70s6 kinase, resulting in the inhibition of autophagy during short-term busulfan treatment. (2) mTOR mediates autophagy with p53 together, to regulate the fate of SPCs. Collectively, observations from this study indicate that moderate autophagy effectively protects SPCs from the stress of chemotherapy, which may provide an important hint for fertility protection in clinic.