Tan Shuai, He Huizhen, Li Yuxin, Shang Mingyue, Cao Yaofang, Zou Dongmei, Hu Ronghua, Hui Wuhan, Chang Xiaoli, Ni Jing, Ma Qiang, Su Li, Sun Jing, He Wanxue, Feng Xingmin, Sun Wanling
Department of Hematology, Xuanwu Hospital, Capital Medical University, Beijing, China.
Department of Pulmonary and Critical Care Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China.
Front Oncol. 2025 Jun 9;15:1568169. doi: 10.3389/fonc.2025.1568169. eCollection 2025.
Acquired aplastic anemia (AA) is a bone marrow failure syndrome characterized by pancytopenia and decreased hematopoietic stem and progenitor cells (HSPCs) in the bone marrow, it can be either congenital or acquired, predominantly affecting adolescents and the elderly, with higher incidence in Asia compared to Europe and America. Current treatment options include allogeneic hematopoietic stem cell transplantation or immunosuppressive agents, yet proximately a third of patients fail to reach long-term survival. AA is primarily driven by immune-mediated destruction of HSPCs, initiated by self-activated T cells. Early stages feature a Th1 response, which later shifts to Th17 and effector memory CD8 T cells. Key cytokines including interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) play crucial roles in this immune dysregulation, influencing HSPCs and contributing to bone marrow failure. Furthermore, bone marrow macrophages (MΦ), particularly M1 subtype, are implicated in AA via the TNF-α/TNF-α receptor pathway, leading to T cell activating and subsequent HSPC damage. Interestingly, MΦ with high expression of IL-27Ra have been demonstrated to contribute to HSPC destruction in AA murine models. Beyond their role in thrombosis, platelets also participate in immune regulation. Some studies suggest that platelet may modulate T cell responses through mechanisms such as Akt-PGC1α-TFAM pathway or PF4-mediated activity, which could play a role in AA. However, direct evidence connecting platelet regulation to T cell-mediated HSPC damage is limited, and current research has largely focuses on CD8 T cells. Moving forward, it is essential to investigate the interactions between platelets, CD4 T cells, and mitochondrial energy metabolism. In this review, we propose that platelet-derived factors such as PF4 and TGFβ may activate mitochondrial pathways, influencing T cell activation and leading to HSPC destruction in AA. This hypothesis could provide new insights into the molecular mechanisms of AA and pave the way for novel therapeutic strategies (Highlight).
获得性再生障碍性贫血（AA）是一种骨髓衰竭综合征，其特征为全血细胞减少以及骨髓中造血干细胞和祖细胞（HSPCs）数量减少。它可以是先天性的，也可以是后天获得的，主要影响青少年和老年人，亚洲地区的发病率高于欧美地区。目前的治疗选择包括异基因造血干细胞移植或免疫抑制剂，但仍有近三分之一的患者无法实现长期生存。AA主要由免疫介导的HSPCs破坏驱动，由自激活的T细胞引发。早期阶段以Th1反应为特征，随后转变为Th17和效应记忆CD8 T细胞。关键细胞因子，包括干扰素-γ（IFN-γ）和肿瘤坏死因子-α（TNF-α），在这种免疫失调中起关键作用，影响HSPCs并导致骨髓衰竭。此外，骨髓巨噬细胞（MΦ），特别是M1亚型，通过TNF-α/TNF-α受体途径参与AA，导致T细胞活化及随后的HSPC损伤。有趣的是，在AA小鼠模型中，高表达IL-27Ra的MΦ已被证明会导致HSPC破坏。除了在血栓形成中的作用外，血小板也参与免疫调节。一些研究表明，血小板可能通过Akt-PGC1α-TFAM途径或PF4介导的活性等机制调节T细胞反应，这可能在AA中发挥作用。然而，将血小板调节与T细胞介导的HSPC损伤联系起来的直接证据有限，目前的研究主要集中在CD8 T细胞上。展望未来，研究血小板、CD4 T细胞和线粒体能量代谢之间的相互作用至关重要。在本综述中，我们提出血小板衍生因子如PF4和TGFβ可能激活线粒体途径，影响T细胞活化并导致AA中的HSPC破坏。这一假设可能为AA的分子机制提供新的见解，并为新的治疗策略铺平道路（重点）。
