Red blood cells supply the oxygen required for all human cells and are in demand for emerging blood-loss therapy. Here we identified N6-methyl-2′-deoxyadenosine (6mdA) as an agonist that promotes the hyperproliferation of burst-forming unit erythroid (BFU-E) progenitor cells. In addition, 6mdA represses the apoptosis of erythroid progenitor cells (EPCs). Combined use of with SCF and EPO enabled cultures of isolated BFU-E to be expanded up to 5,000-fold. Transcriptome analysis showed that 6mdA upregulates the expression of the EPC-associated factors c-Kit, Myb, and Gata2 and downregulates that of the erythroid maturation-related transcription factors Gata1, Spi1, and Klf1. Mechanistic studies suggested that 6mdA enhances and prolongs the activation of erythropoiesis-associated master gene c-Kit and its downstream signaling, leading to expansion and accumulation of EPCs. Collectively, we demonstrate that 6mdA can efficiently stimulate the EPC hyperproliferation and provide a new regenerative medicine recipe to improve generation of red blood cells.

中文翻译：

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N6-甲基-2′-脱氧腺苷促进红细胞生成中 BFU-E 祖细胞的自我更新

红细胞提供所有人体细胞所需的氧气，并且是新兴失血疗法所需要的。在这里，我们确定 N6-甲基-2'-脱氧腺苷 (6mdA) 是一种激动剂，可促进突发形成单位红系 (BFU-E) 祖细胞的过度增殖。此外，6mdA 还可抑制红系祖细胞 (EPC) 的凋亡。与 SCF 和 EPO 结合使用，可使分离的 BFU-E 培养物扩增至 5,000 倍。转录组分析显示，6mdA 上调 EPC 相关因子 c-Kit、Myb 和 Gata2 的表达，下调红细胞成熟相关转录因子 Gata1、Spi1 和 Klf1 的表达。机制研究表明，6mdA 增强并延长红细胞生成相关主基因 c-Kit 及其下游信号传导的激活，导致 EPC 的扩增和积累。总的来说，我们证明 6mdA 可以有效刺激 EPC 过度增殖，并提供一种新的再生医学配方来改善红细胞的生成。