HSPG2 could promote normal haematopoiesis in acute myeloid leukaemia patients after complete remission by repairing bone marrow endothelial progenitor cells

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-02-06 DOI:10.1002/ctm2.70220

Chen-Yuan Li, Zhen-Kun Wang, Tong Xing, Meng-Zhu Shen, Xin-Yan Zhang, Dan-Dan Chen, Yu Wang, Hao Jiang, Qian Jiang, Xiao-Jun Huang, Yuan Kong

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Abstract

Background

Even after achieving complete remission (CR), many acute myeloid leukaemia (AML) patients suffer from poor haematopoietic recovery after chemotherapy. Previous studies have shown that the damage of bone marrow endothelial progenitor cell (BM EPC) hinders haematopoietic recovery after chemotherapy in mice. Therefore, elucidation of the mechanism and repair strategy of chemotherapy-induced BM EPC damage is urgent needed.

Methods

The prospective case–control study enrolled 40 AML patients after CR (CR patients), who received idarubicin and cytarabine (IA) regimen (n = 20), or homoharringtonine, aclarubicin and cytarabine (HAA) regimen (n = 20) as induction chemotherapy, and their age-matched healthy controls (HCs, n = 20). The HSPG2 expression level in BM EPCs and BM plasma were determined via flow cytometry and enzyme-linked immunosorbent assays. The BM EPC's functions were evaluated by apoptosis, reactive oxygen species (ROS) level, migration and tube formation assays. The haematopoiesis-supporting ability and leukaemia cell-supporting ability of BM EPCs were assessed through coculture assay. Moreover, RNA sequencing and qPCR were performed to further explore the underlying mechanism.

Results

HSPG2 levels decreased in both the BM plasma and BM EPCs of CR patients after IA and HAA induction chemotherapy. Moreover, the BM EPC's functions of CR patients were reduced. In vitro experiments demonstrated that the HSPG2 gene knockdown or cytosine arabinoside treatment led to BM EPC dysfunction, whereas the HSPG2 treatment promoted repair of the BM EPC function in vitro. In addition, we found that the HSPG2 treatment restored the BM EPC function from CR patients without affecting their leukaemia cell-supporting ability. Mechanistically, BM EPC functions and haematopoietic regulation-related genes were significantly decreased after the HSPG2 gene knockdown.

Conclusion

Our findings demonstrate a significant role of HSPG2 in BM EPC functions. This discovery uncovers that HSPG2 is a potential therapeutic target for promoting the BM EPC function of AML-CR patients after chemotherapy.

Highlights

The HSPG2 level in the BM EPCs of AML-CR patients was decreased, which was related to the reduced BM EPC function.
HSPG2 knockdown or Ara-C intervention reduced the HSPG2 level and led to BM EPC dysfunction, which could be restored by HSPG2 treatment in vitro.
HSPG2 treatment restored the BM EPC function of AML-CR patients without affecting their leukaemia cell-supporting ability.

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HSPG2可通过修复骨髓内皮祖细胞促进急性髓系白血病患者完全缓解后的正常造血

背景：即使在完全缓解（CR）后，许多急性髓性白血病（AML）患者在化疗后的造血功能恢复不佳。既往研究表明，骨髓内皮祖细胞（bmepc）损伤会阻碍小鼠化疗后造血功能的恢复。因此，迫切需要阐明化疗诱导的骨髓EPC损伤的机制和修复策略。方法采用前瞻性病例对照研究，纳入40例CR后AML患者（CR患者），接受依达柔比星+阿糖胞苷（IA）方案（n = 20），或同质杉碱+阿克柔比星+阿糖胞苷（HAA）方案（n = 20）作为诱导化疗，并与年龄匹配的健康对照（hc, n = 20）。采用流式细胞术和酶联免疫吸附法检测骨髓EPCs和血浆中HSPG2的表达水平。通过细胞凋亡、活性氧（ROS）水平、迁移和成管实验来评估BM EPC的功能。通过共培养法评价骨髓内皮祖细胞的造血支持能力和白血病细胞支持能力。此外，通过RNA测序和qPCR进一步探索其潜在机制。结果IA和HAA诱导化疗后，CR患者BM血浆和BM EPCs中HSPG2水平均下降。此外，CR患者的BM EPC功能降低。体外实验表明，HSPG2基因敲低或阿拉伯糖胞嘧啶处理可导致BM EPC功能障碍，而HSPG2处理可促进BM EPC功能的修复。此外，我们发现HSPG2治疗恢复了CR患者的BM EPC功能，而不影响其白血病细胞支持能力。机制上，HSPG2基因敲除后，BM EPC功能和造血调节相关基因显著降低。结论HSPG2在骨髓EPC功能中起重要作用。这一发现揭示了HSPG2是促进AML-CR患者化疗后BM EPC功能的潜在治疗靶点。AML-CR患者BM EPCs中HSPG2水平降低，这与BM EPC功能降低有关。HSPG2敲低或Ara-C干预可降低HSPG2水平，导致BM EPC功能障碍，HSPG2处理可使其在体外恢复。HSPG2治疗可恢复AML-CR患者骨髓EPC功能，但不影响其白血病细胞支持能力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.