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Repair of dysfunctional bone marrow endothelial cells alleviates aplastic anemia

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Abstract

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.

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Acknowledgements

This work was supported by the National Key Research and Development Program of China (2021YFA1100900, 2022YFA1103300), the National Natural Science Foundation of China (82070188, 82270229, 81930004), Beijing Natural Science Foundation (7232181), and Peking University People’s Hospital Scientific Research Development Funds (RDGS2022-04). The authors thank all of the core facilities at the Peking University Institute of Hematology for patient care and sample collection. We appreciate Professor Neal S Young and his team provided generous instruction in establishing the AA mouse model. The authors thank Cai-Wen Duan from Shanghai Jiao Tong University School of Medicine for excellent assistance with the immunofluorescent staining, and thank Wei-Li Yao for excellent assistance with drawing the graphical abstract.

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  1. 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

    Shu-Qian Tang, Tong Xing, Zhong-Shi Lyu, Li-Ping Guo, Mi Liang, Chen-Yuan Li, Yuan-Yuan Zhang, Yu Wang, Lan-Ping Xu, Xiao-Hui Zhang, Xiao-Jun Huang & Yuan Kong

  2. Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China

    Tong Xing & Xiao-Jun Huang

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Tang, SQ., Xing, T., Lyu, ZS. et al. Repair of dysfunctional bone marrow endothelial cells alleviates aplastic anemia. Sci. China Life Sci. 66, 2553–2570 (2023). https://doi.org/10.1007/s11427-022-2310-x

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