2025 Volume No 50 – pages 137-151
Title: Hypoxia-derived mesenchymal stem-cell exosomes delivering naringin enhance osteoblast migration and fracture healing by upregulating integrin β1 via the BDNF-TrkB/ERK1/2 signaling pathway |
Authors: RF Yao, YY Luo, HL Tian |
Address: Department of Orthopaedics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, 250014 Jinan, Shandong, China |
E-mail: tianhlai at 163.com |
Abstract: Background: The paracrine mechanism of mesenchymal stem cells (MSCs) is receiving extensive attention, and exosomes are positioned as the key mediators. MSCs subjected to hypoxic preconditioning exhibit notably enhanced paracrine functions. Recent studies have revealed that Naringin (Ng), acting through the paracrine actions of MSCs, can promote osteoblast migration and bone-fracture healing, although the detailed mechanisms behind this effect remain to be fully elucidated. This study aimed to explore the effect of hypoxia pretreatment on the bioactivity of exosomes and fracture healing through Ng regulation. Methods: Exosome nanoparticles containing Ng were identified by transmission electron microscopy and nanoparticle tracking analysis. In vivo, a fracture mice model was established by staining Ki67 CD31+ and Emcn CD31+ positive cells. Bone healing after normoxia, hypoxia, normoxia + Ng, and hypoxia + Ng treatment was evaluated. In vitro, the effects of different interventions on human umbilical cord MSCs (HucMSCs) were evaluated experimentally by cell counting kit-8 (CCK8), 5-ethynyl-2′-deoxyuridine (EdU) staining, cell migration, Transwell invasion, and tube-formation assay. Tropomyosin receptor kinase B (TrkB), brain-derived neurotrophic factor (BDNF), and integrin β1, respectively were silenced to explore the possible mechanisms promoting bone healing. Results: Results showed that Ng-rich exosomes significantly promoted osteoblast migration and bone healing under hypoxia conditions (p < 0.001). Under hypoxia conditions, exosomes derived from MSCs can be used as carriers for Ng delivery. These exosomes targeted the BDNF-mediated TrkB/extracellular regulated protein kinases (ERK)1/2 signaling pathway and upregulated integrin β1 expression. Conclusions: These findings unveiled the potential mechanisms by which hypoxia-conditioned MSC-derived exosomes wrapped in Ng promoted osteoblast migration and bone-fracture healing. A theoretical foundation was also provided for using MSC-derived exosomes as a novel bone-repair treatment strategy. |
Keywords: Mesenchymal stem cell, hypoxia, human umbilical vein endothelial cells, osteoblast migration, bone healing. |
Publication date: 24th April 2025 |
Copyright policy: © 2025 The Author(s). Published by Forum Multimedia Publishing, LLC. This article is distributed in accordance with Creative Commons Attribution Licence (http://creativecommons.org/licenses/by/4.0/). |
Article download: Pages 137-151 (PDF file) |
