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Background <p>Steroid-induced osteonecrosis of the femoral head (SONFH) is characterized by impaired angiogenesis and bone remodeling, ultimately leading to joint dysfunction. Exosomes derived from bone marrow mesenchymal stem cells (BMSCs) carry bioactive molecules, including circular RNAs (circRNAs), which play crucial roles in regulating angiogenesis and tissue repair. This study investigated the role of a novel BMSC-derived exosomal circRNA (novel_circ_0001686) in promoting angiogenesis through a competing endogenous RNA (ceRNA) mechanism, targeting the miR-34a-5p/Piezo1 axis.</p> Methods <p>This study employed a comprehensive approach to determine the roles of circRNAs in BMSC-derived exosomes from patients with SONFH. High-throughput sequencing identified circRNA profiles, with a focus on novel_circ_0001686. Its structure and expression were confirmed via Sanger sequencing, qRT-PCR, agarose gel electrophoresis, and ribonuclease R (RNase R) treatment, while its subcellular localization was determined through fluorescence in situ hybridization (FISH) and nuclear/cytoplasmic fractionation. The biological effects of novel_circ_0001686 were explored using human umbilical vein endothelial cells (HUVECs) with lentivirus-mediated overexpression and knockdown to assess its impact on cell proliferation, migration, apoptosis, and angiogenesis. Exosome functionality was investigated using co-culture systems, exosome uptake assays, and GW4869 treatment to evaluate the role of exosome-mediated transfer in these processes. Mechanistic studies involved miRNA prediction tools, dual-luciferase reporter assays, RNA immunoprecipitation (RIP), RNA antisense purification (RAP), and rescue experiments. Angiogenic effects were further evaluated using ex vivo aortic ring and in vivo chicken chorioallantoic membrane (CAM) assays.</p> Results <p>Sequencing identified 664 circRNAs in BMSC-derived exosomes, including 113 novel circRNAs. Novel_circ_0001686, which was significantly downregulated in SONFH exosomes, exhibited hallmark features of circRNAs, including a stable circular structure and cytoplasmic localization. Functional studies showed that it significantly enhanced HUVEC proliferation, migration, anti-apoptotic activity, and tube formation. Mechanistic analyses revealed that novel_circ_0001686 acts as a ceRNA, sponging miR-34a-5p and reducing its suppressive effect on Piezo1. Rescue experiments confirmed that miR-34a-5p mimic or Piezo1 knockdown abolished the pro-angiogenic effects of novel_circ_0001686. Ex vivo aortic ring assays and the in vivo CAM model substantiated the ability of exosomal novel_circ_0001686 to enhance microvessel sprouting and capillary formation.</p> Conclusions <p>This study provides the first reported circRNA profile of BMSC-derived exosomes in SONFH, identifying novel_circ_0001686 as a key regulator of angiogenesis. By acting through the novel_circ_0001686/miR-34a-5p/Piezo1 axis, it enhances endothelial function and vascular remodeling. These findings imply that novel_circ_0001686 is a promising therapeutic target, underscoring the potential of exosome-based strategies for restoring vascularization and bone homeostasis in SONFH.</p>

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A novel BMSC-derived Exosomal circrna promotes angiogenesis by targeting miR-34a-5p to regulate Piezo1

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月25日

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  • Tingyu Wu,
  • Yinxue Zhou,
  • Yaping Jiang,
  • Xiaoxia Li,
  • Weipeng Shi,
  • Zehua Wang,
  • Sijia Guo,
  • Yingzhen Wang,
  • Tao Li

摘要

Background

Steroid-induced osteonecrosis of the femoral head (SONFH) is characterized by impaired angiogenesis and bone remodeling, ultimately leading to joint dysfunction. Exosomes derived from bone marrow mesenchymal stem cells (BMSCs) carry bioactive molecules, including circular RNAs (circRNAs), which play crucial roles in regulating angiogenesis and tissue repair. This study investigated the role of a novel BMSC-derived exosomal circRNA (novel_circ_0001686) in promoting angiogenesis through a competing endogenous RNA (ceRNA) mechanism, targeting the miR-34a-5p/Piezo1 axis.

Methods

This study employed a comprehensive approach to determine the roles of circRNAs in BMSC-derived exosomes from patients with SONFH. High-throughput sequencing identified circRNA profiles, with a focus on novel_circ_0001686. Its structure and expression were confirmed via Sanger sequencing, qRT-PCR, agarose gel electrophoresis, and ribonuclease R (RNase R) treatment, while its subcellular localization was determined through fluorescence in situ hybridization (FISH) and nuclear/cytoplasmic fractionation. The biological effects of novel_circ_0001686 were explored using human umbilical vein endothelial cells (HUVECs) with lentivirus-mediated overexpression and knockdown to assess its impact on cell proliferation, migration, apoptosis, and angiogenesis. Exosome functionality was investigated using co-culture systems, exosome uptake assays, and GW4869 treatment to evaluate the role of exosome-mediated transfer in these processes. Mechanistic studies involved miRNA prediction tools, dual-luciferase reporter assays, RNA immunoprecipitation (RIP), RNA antisense purification (RAP), and rescue experiments. Angiogenic effects were further evaluated using ex vivo aortic ring and in vivo chicken chorioallantoic membrane (CAM) assays.

Results

Sequencing identified 664 circRNAs in BMSC-derived exosomes, including 113 novel circRNAs. Novel_circ_0001686, which was significantly downregulated in SONFH exosomes, exhibited hallmark features of circRNAs, including a stable circular structure and cytoplasmic localization. Functional studies showed that it significantly enhanced HUVEC proliferation, migration, anti-apoptotic activity, and tube formation. Mechanistic analyses revealed that novel_circ_0001686 acts as a ceRNA, sponging miR-34a-5p and reducing its suppressive effect on Piezo1. Rescue experiments confirmed that miR-34a-5p mimic or Piezo1 knockdown abolished the pro-angiogenic effects of novel_circ_0001686. Ex vivo aortic ring assays and the in vivo CAM model substantiated the ability of exosomal novel_circ_0001686 to enhance microvessel sprouting and capillary formation.

Conclusions

This study provides the first reported circRNA profile of BMSC-derived exosomes in SONFH, identifying novel_circ_0001686 as a key regulator of angiogenesis. By acting through the novel_circ_0001686/miR-34a-5p/Piezo1 axis, it enhances endothelial function and vascular remodeling. These findings imply that novel_circ_0001686 is a promising therapeutic target, underscoring the potential of exosome-based strategies for restoring vascularization and bone homeostasis in SONFH.