中国组织工程研究

骨髓微环境中不同细胞对多发性骨髓瘤骨病外泌体环状 RNA 的贡献及相互作用

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于漫亚 ¹ , 崔兴 ²

中国组织工程研究 | 工程化干细胞来源外泌体及囊泡 2026,30(1): 101-110

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中国组织工程研究 |工程化干细胞来源外泌体及囊泡 2026 , 30 (1) : 101 -110

骨髓微环境中不同细胞对多发性骨髓瘤骨病外泌体环状 RNA 的贡献及相互作用

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于漫亚¹, 崔兴²

作者信息

^1.东中医药大学第一临床学院，山东省济南市 250014

^2.山东中医药大学第二附属医院肿瘤中心，山东省济南市 250001

Contribution and interaction of various cells in bone marrow microenvironment to exosomal circular RNA associated with multiple myeloma bone disease

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出版时间: 2026-01-08 doi: 10.12307/2025.567

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摘要

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背景：多发性骨髓瘤骨病是多发性骨髓瘤的严重并发症，其发病机制与骨髓微环境失调密切相关。外泌体环状RNA因高稳定性、高丰度、高特异性、高保守性等特点，正逐渐成为液体活检的焦点。在多发性骨髓瘤骨病中，外泌体环状RNA的作用尚缺乏相关研究。随着单细胞RNA测序技术的发展，明确骨髓微环境中各类型细胞对多发性骨髓瘤骨病相关外泌体环状RNA的贡献及相互作用，有助于为多发性骨髓瘤骨病的诊疗提供新的生物标志物。目的：初步明确多发性骨髓瘤骨病相关外周血外泌体环状RNA的骨髓微环境来源细胞，并在单细胞水平上探究骨髓微环境中各细胞相互作用对多发性骨髓瘤骨病的影响。方法：对6例多发性骨髓瘤骨病患者和5名健康志愿者的外周血外泌体进行高通量测序，筛选差异环状RNA，并进行GO和KEGG富集分析。从GEO数据库中获取多发性骨髓瘤骨病患者的骨髓单细胞RNA测序数据集GSE271107，对其中的4例多发性骨髓瘤骨病患者数据进行整合，完成质控和过滤后，利用Harmony法去除批次效应，UMAP进行亚群聚类，SingleR自动注释后手动矫正细胞群，CellChat对单细胞RNA测序数据中的细胞间通讯进行推断和可视化，分析配体、受体间的相互作用。结果与结论：①相较于健康志愿者，多发性骨髓瘤骨病患者外周血外泌体中1 265个环状RNA表达水平显著上调；②GO和KEGG分析差异环状RNA的亲本基因主要富集在神经系统发育、癌症中的通路、PI3K-Akt信号通路、Hippo信号通路、致心律失常性右心室心肌病、扩张型心肌病等，这与骨髓瘤细胞的增殖、黏附、迁移、归巢，以及多发性骨髓瘤相关并发症(如多发性骨髓瘤骨病、周围神经病变、心脏事件)关系密切；③多发性骨髓瘤骨病相关差异环状RNA的亲本基因主要来源于骨髓微环境中的T细胞/自然杀伤细胞、B细胞和单核/巨噬细胞，通过调节多种细胞因子的分泌影响破骨细胞功能；④单核细胞/巨噬细胞作为破骨细胞前体细胞与骨髓瘤细胞及其他免疫细胞间均有相互作用，MIF通路是其参与的主要通路。以上结果初步明确了多发性骨髓瘤骨病相关外周血外泌体环状RNA的骨髓微环境来源细胞，并发现单核/巨噬细胞与骨髓瘤细胞及免疫细胞间的MIF通路配体-受体相互作用可能是多发性骨髓瘤骨病发生的重要因素。

关键词

多发性骨髓瘤骨病 / 外泌体 / 环状RNA / 单细胞RNA测序 / 骨髓微环境 / 破骨细胞 / PI3K-Akt信号通路 / Hippo信号通路 / 工程化外泌体

Abstract

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BACKGROUND: Multiple myeloma bone disease is a serious complication of multiple myeloma, and its pathogenesis is closely related to the dysregulation of the bone marrow microenvironment. Peripheral blood exosomes are secreted by various cell types and can reflect a variety of information such as the tumor microenvironment. Exosomal circular RNA is gradually becoming the focus of liquid biopsy due to its high stability, high abundance, high specificity, and high conservation. In multiple myeloma bone disease, there is still a lack of relevant research on the role of exosomal circular RNAs. With the development of single-cell RNA sequencing technology, clarifying the contribution of each cell type in the bone marrow microenvironment to multiple myeloma bone disease-related exosomal circular RNAs and the interaction between each cell type will help provide new biomarkers for the diagnosis and treatment of multiple myeloma bone disease. OBJECTIVE: To preliminarily determine which cells in the bone marrow microenvironment the multiple myeloma bone disease-related peripheral blood exosomal circular RNAs originated from, and explore the effects of cell interactions in the bone marrow microenvironment on multiple myeloma bone disease at the single-cell level. METHODS: Peripheral blood exosomes from six multiple myeloma bone disease patients and five healthy controls were collected for high-throughput sequencing, differently expressed circular RNAs were screened, and GO and KEGG enrichment analyses were performed. The bone marrow single-cell RNA sequencing dataset GSE271107 was obtained from the GEO database. The data of four multiple myeloma bone disease patients were integrated. After quality control and filtering, the batch effect was removed by Harmony method. Subgroup clustering was performed by UMAP, and cell groups were manually corrected after automatic annotation by SingleR. CellChat was used to infer and visualize the intercellular communication in single-cell RNA sequencing data, and analyze the interaction between ligands and receptors. RESULTS AND CONCLUSION: (1) Compared with healthy controls, the expression levels of 1 265 circular RNAs in peripheral blood exosomes of multiple myeloma bone disease patients were significantly upregulated. (2) GO and KEGG analyses suggested that the parent genes of differently expressed circular RNAs were mainly enriched in pathways in nervous system development, pathways in cancer, PI3K-Akt signaling pathway, Hippo signaling pathway, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, etc., which were closely related to the proliferation, adhesion, migration, and homing of myeloma cells, and multiple myeloma-related complications (such as multiple myeloma bone disease, peripheral neuropathy, and cardiac events). (3) The parent genes of multiple myeloma bone disease-related differential circular RNAs were mainly derived from T cells/natural killer cells, B cells and monocytes/macrophages in the bone marrow microenvironment, which affected osteoclast function by regulating the secretion of multiple cytokines. (4) Monocytes/macrophages, as osteoclast precursor cells, interacted with tumor cells and other immune cells. The MIF pathway was the main pathway involved. The above data preliminarily identified the source cells of multiple myeloma bone disease-related peripheral blood exosomal circular RNA in the bone marrow microenvironment, and found that the ligand-receptor interaction of the MIF pathway between monocytes/macrophages and tumor cells and immune cells may be an important factor in the occurrence of multiple myeloma bone disease.

Key words

multiple myeloma bone disease / exosome / circular RNA / single-cell RNA sequencing / bone marrow microenvironment / osteoclast / PI3K-Akt signaling pathway / Hippo signaling pathway / engineered exosome

引用本文

于漫亚, 崔兴. 骨髓微环境中不同细胞对多发性骨髓瘤骨病外泌体环状 RNA 的贡献及相互作用. 中国组织工程研究, 2026 , 30 (1) : 101 -110 . DOI: 10.12307/2025.567

. Contribution and interaction of various cells in bone marrow microenvironment to exosomal circular RNA associated with multiple myeloma bone disease[J]. Chinese Journal of Tissue Engineering Research, 2026 , 30 (1) : 101 -110 . DOI: 10.12307/2025.567

基金

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国家自然科学基金面上项目
山东省自然科学基金创新发展联合基金

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2026年第30卷第1期

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doi: 10.12307/2025.567

首发时间：2025-05-30
出版时间：2026-01-08

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录用日期：2024-12-23

基金

国家自然科学基金面上项目

山东省自然科学基金创新发展联合基金

作者信息

^1.东中医药大学第一临床学院，山东省济南市 250014

^2.山东中医药大学第二附属医院肿瘤中心，山东省济南市 250001

通讯作者:

崔兴: 崔兴，博士，主任医师，教授，博士生导师，山东中医药大学第二附属医院肿瘤中心，山东省济南市 250001

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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