Aoyama Yumi, Yamazaki Hiromi, Nishimura Koutarou, Nomura Masaki, Shigehiro Tsukasa, Suzuki Takafumi, Zang Weijia, Tatara Yota, Ito Hiromi, Hayashi Yasutaka, Koike Yui, Fukumoto Miki, Tanaka Atsushi, Zhang Yifan, Saika Wataru, Hasegawa Chihiro, Kasai Shuya, Kong Yingyi, Minakuchi Yohei, Itoh Ken, Yamamoto Masayuki, Toyokuni Shinya, Toyoda Atsushi, Ikawa Tomokatsu, Takaori-Kondo Akifumi, Inoue Daichi
Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan.
Department of Hematology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Blood. 2025 Mar 13;145(11):1149-1163. doi: 10.1182/blood.2024025402.
The maintenance of cellular redox balance is crucial for cell survival and homeostasis and is disrupted with aging. Selenoproteins, comprising essential antioxidant enzymes, raise intriguing questions about their involvement in hematopoietic aging and potential reversibility. Motivated by our observation of messenger RNA downregulation of key antioxidant selenoproteins in aged human hematopoietic stem cells (HSCs) and previous findings of increased lipid peroxidation in aged hematopoiesis, we used selenocysteine transfer RNA (tRNASec) gene (Trsp) knockout (KO) mouse model to simulate disrupted selenoprotein synthesis. This revealed insights into the protective roles of selenoproteins in preserving HSC stemness and B-lineage maturation, despite negligible effects on myeloid cells. Notably, Trsp KO exhibited B lymphocytopenia and reduced HSCs' self-renewal capacity, recapitulating certain aspects of aged phenotypes, along with the upregulation of aging-related genes in both HSCs and pre-B cells. Although Trsp KO activated an antioxidant response transcription factor NRF2, we delineated a lineage-dependent phenotype driven by lipid peroxidation, which was exacerbated with aging yet ameliorated by ferroptosis inhibitors such as vitamin E. Interestingly, the myeloid genes were ectopically expressed in pre-B cells of Trsp KO mice, and KO pro-B/pre-B cells displayed differentiation potential toward functional CD11b+ fraction in the transplant model, suggesting that disrupted selenoprotein synthesis induces the potential of B-to-myeloid switch. Given the similarities between the KO model and aged wild-type mice, including ferroptosis vulnerability, impaired HSC self-renewal and B-lineage maturation, and characteristic lineage switch, our findings underscore the critical role of selenoprotein-mediated redox regulation in maintaining balanced hematopoiesis and suggest the preventive potential of selenoproteins against aging-related alterations.
细胞氧化还原平衡的维持对细胞存活和稳态至关重要，且会随着衰老而被破坏。硒蛋白包含必需的抗氧化酶，这引发了关于它们在造血衰老中的作用及其潜在可逆性的有趣问题。基于我们对老年人类造血干细胞（HSC）中关键抗氧化硒蛋白信使RNA下调的观察以及先前关于老年造血中脂质过氧化增加的研究结果，我们使用硒代半胱氨酸转运RNA（tRNASec）基因（Trsp）敲除（KO）小鼠模型来模拟硒蛋白合成的破坏。这揭示了硒蛋白在维持HSC干性和B系成熟中的保护作用，尽管对髓系细胞的影响可忽略不计。值得注意的是，Trsp KO表现出B淋巴细胞减少和HSC自我更新能力降低，概括了衰老表型的某些方面，同时HSC和前B细胞中与衰老相关基因上调。尽管Trsp KO激活了抗氧化反应转录因子NRF2，但我们描绘了一种由脂质过氧化驱动的谱系依赖性表型，这种表型随着衰老而加剧，但可被维生素E等铁死亡抑制剂改善。有趣的是，髓系基因在Trsp KO小鼠的前B细胞中异位表达，并且KO前B/前B细胞在移植模型中显示出向功能性CD11b+部分分化的潜力，这表明硒蛋白合成的破坏诱导了B向髓系转换的潜力。鉴于KO模型与老年野生型小鼠之间的相似性，包括铁死亡易感性、HSC自我更新和B系成熟受损以及特征性谱系转换，我们的研究结果强调了硒蛋白介导的氧化还原调节在维持平衡造血中的关键作用，并表明硒蛋白对衰老相关改变的预防潜力。
