Zhang Xin-Yan, Guo Li-Ping, Wang Ya-Zhe, Jia Jin-Song, Liang Mi, Shen Meng-Zhu, Wang Zhen-Kun, Zhang Zhi-Wei, Li Chen-Yuan, Lyu Zhong-Shi, Xing Tong, Zhang Yuan-Yuan, Huang Xiao-Jun, Kong Yuan
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China.
Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
Exp Mol Med. 2025 Jun;57(6):1324-1338. doi: 10.1038/s12276-025-01483-4. Epub 2025 Jun 30.
Aplastic anemia (AA) is a life-threatening bone marrow (BM) failure syndrome characterized by pancytopenia. Recent studies revealed that dysfunctional endothelial progenitor cells (EPCs), critical components of the BM microenvironment, are involved in hematopoietic-dysfunction-related diseases, including AA. However, the mechanism underlying EPC damage in AA remains unknown. Here we find that transforming growth factor-β (TGF-β) signaling is hyperactive in dysfunctional AA EPCs with impaired hematopoietic support and immune regulatory ability, and TGF-β inhibition promotes hematopoiesis and immune rebalance by repairing dysfunctional EPCs. Through impaired EPC and AA murine models, we validated that TGF-β inhibition restores EPC dysfunction to improve hematopoiesis and immune status in vitro and in vivo. RNA sequencing and real-time quantitative polymerase chain reaction provided further validation. These results indicate that dysfunctional BM EPCs with hyperactive TGF-β signaling are involved in AA. TGF-β inhibition promotes multilineage hematopoiesis recovery and immune balance by repairing dysfunctional EPCs, providing a potential therapeutic strategy for AA.
再生障碍性贫血（AA）是一种以全血细胞减少为特征的危及生命的骨髓（BM）衰竭综合征。最近的研究表明，功能失调的内皮祖细胞（EPCs）是BM微环境的关键组成部分，参与包括AA在内的造血功能障碍相关疾病。然而，AA中EPC损伤的潜在机制仍不清楚。在这里，我们发现转化生长因子-β（TGF-β）信号在造血支持和免疫调节能力受损的功能失调的AA EPCs中过度活跃，TGF-β抑制通过修复功能失调的EPCs促进造血和免疫重新平衡。通过EPC损伤和AA小鼠模型，我们验证了TGF-β抑制在体外和体内恢复EPC功能障碍，以改善造血和免疫状态。RNA测序和实时定量聚合酶链反应提供了进一步的验证。这些结果表明，TGF-β信号过度活跃的功能失调的BM EPCs参与了AA。TGF-β抑制通过修复功能失调的EPCs促进多谱系造血恢复和免疫平衡，为AA提供了一种潜在的治疗策略。
