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, 100044, China.
Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China.
Sci China Life Sci. 2023 Nov;66(11):2553-2570. doi: 10.1007/s11427-022-2310-x. Epub 2023 Jun 5.
Aplastic anemia (AA) is a life-threatening disease characterized by bone marrow (BM) failure and pancytopenia. As an important component of the BM microenvironment, endothelial cells (ECs) play a crucial role in supporting hematopoiesis and regulating immunity. However, whether impaired BM ECs are involved in the occurrence of AA and whether repairing BM ECs could improve hematopoiesis and immune status in AA remain unknown. In this study, a classical AA mouse model and VE-cadherin blocking antibody that could antagonize the function of ECs were used to validate the role of BM ECs in the occurrence of AA. N-acetyl-L-cysteine (NAC, a reactive oxygen species scavenger) or exogenous EC infusion was administered to AA mice. Furthermore, the frequency and functions of BM ECs from AA patients and healthy donors were evaluated. BM ECs from AA patients were treated with NAC in vitro, and then the functions of BM ECs were evaluated. We found that BM ECs were significantly decreased and damaged in AA mice. Hematopoietic failure and immune imbalance became more severe when the function of BM ECs was antagonized, whereas NAC or EC infusion improved hematopoietic and immunological status by repairing BM ECs in AA mice. Consistently, BM ECs in AA patients were decreased and dysfunctional. Furthermore, dysfunctional BM ECs in AA patients led to their impaired ability to support hematopoiesis and dysregulate T cell differentiation toward proinflammatory phenotypes, which could be repaired by NAC in vitro. The reactive oxygen species pathway was activated, and hematopoiesis- and immune-related signaling pathways were enriched in BM ECs of AA patients. In conclusion, our data indicate that dysfunctional BM ECs with impaired hematopoiesis-supporting and immunomodulatory abilities are involved in the occurrence of AA, suggesting that repairing dysfunctional BM ECs may be a potential therapeutic approach for AA patients.
再生障碍性贫血（AA）是一种危及生命的疾病，其特征为骨髓（BM）衰竭和全血细胞减少。作为 BM 微环境的重要组成部分，内皮细胞（ECs）在支持造血和调节免疫方面发挥着关键作用。然而，受损的 BM EC 是否参与 AA 的发生，以及修复 BM EC 是否可以改善 AA 中的造血和免疫状态尚不清楚。在这项研究中，使用了经典的 AA 小鼠模型和 VE-cadherin 阻断抗体（可以拮抗 EC 的功能）来验证 BM EC 在 AA 发生中的作用。给 AA 小鼠给予 N-乙酰-L-半胱氨酸（NAC，一种活性氧清除剂）或外源性 EC 输注。此外，评估了 AA 患者和健康供体的 BM EC 的频率和功能。体外将 NAC 处理 AA 患者的 BM EC，然后评估 BM EC 的功能。我们发现 AA 小鼠的 BM EC 明显减少和受损。拮抗 BM EC 功能时，造血衰竭和免疫失衡变得更加严重，而 NAC 或 EC 输注通过修复 AA 小鼠的 BM EC 改善了造血和免疫状态。一致地，AA 患者的 BM EC 减少且功能失调。此外，AA 患者功能失调的 BM EC 导致其支持造血和调节 T 细胞分化为促炎表型的能力受损，这可以通过体外的 NAC 修复。AA 患者的 BM EC 中激活了活性氧途径，并且造血和免疫相关信号通路被富集。总之，我们的数据表明，具有受损的造血支持和免疫调节能力的功能失调的 BM EC 参与了 AA 的发生，这表明修复功能失调的 BM EC 可能是 AA 患者的一种潜在治疗方法。
