Bioactive glass-elicited stem cell-derived extracellular vesicles regulate M2 macrophage polarization and angiogenesis to improve tendon regeneration and functional recovery

Hongtao Xu; Yanlun Zhu; Allen Wei-Ting Hsiao; Jiankun Xu; Wenxue Tong; Liang Chang; Xuerao Zhang; Yi-Fan Chen; Jie Li; Wei Chen; Yingze Zhang; Hon Fai Chan; Chien-Wei Lee

doi:10.1016/j.biomaterials.2023.121998

Bioactive glass-elicited stem cell-derived extracellular vesicles regulate M2 macrophage polarization and angiogenesis to improve tendon regeneration and functional recovery

Biomaterials. 2023 Mar:294:121998. doi: 10.1016/j.biomaterials.2023.121998. Epub 2023 Jan 10.

Authors

Hongtao Xu¹, Yanlun Zhu², Allen Wei-Ting Hsiao³, Jiankun Xu⁴, Wenxue Tong⁵, Liang Chang⁶, Xuerao Zhang⁷, Yi-Fan Chen⁸, Jie Li⁹, Wei Chen¹⁰, Yingze Zhang¹¹, Hon Fai Chan¹², Chien-Wei Lee¹³

Affiliations

¹ Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Musculoskeletal Research Laboratory, Department of Orthopedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China; Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China. Electronic address: xhtsmed@gmail.com.
² Institute for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China; Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China. Electronic address: yanlunzhu@163.com.
³ Musculoskeletal Research Laboratory, Department of Orthopedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China. Electronic address: allenhwt1989@link.cuhk.edu.hk.
⁴ Musculoskeletal Research Laboratory, Department of Orthopedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China; Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China. Electronic address: jiankunxu@cuhk.edu.hk.
⁵ Musculoskeletal Research Laboratory, Department of Orthopedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China; Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China. Electronic address: twxleo@cuhk.edu.hk.
⁶ Musculoskeletal Research Laboratory, Department of Orthopedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China; Innovative Orthopaedic Biomaterial and Drug Translational Research Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China. Electronic address: liangch@link.cuhk.edu.hk.
⁷ Institute for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China; Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China. Electronic address: 1155165808@link.cuhk.edu.hk.
⁸ The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Master Program in Clinical Genomics and Proteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan. Electronic address: evan.yifan@tmu.edu.tw.
⁹ Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. Electronic address: lijiesurg@126.com.
¹⁰ Department of Orthopedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, China. Electronic address: surgeonchenwei@126.com.
¹¹ Department of Orthopedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, China. Electronic address: dryingzezhang@163.com.
¹² Institute for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China; Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China; Center for Neuromusculoskeletal Restorative Medicine, Hong Kong SAR, China. Electronic address: honfaichan@cuhk.edu.hk.
¹³ Center for Translational Genomics & Regenerative Medicine Research, China Medical University Hospital, China Medical University, Taichung, Taiwan. Electronic address: icehikki@gmail.com.

PMID: 36641814
DOI: 10.1016/j.biomaterials.2023.121998

Abstract

Effective countermeasures for tendon injury remains unsatisfactory. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs)-based therapy via regulation of Mφ-mediated angiogenesis has emerged as a promising strategy for tissue regeneration. Still, approaches to tailor the functions of EVs to treat tendon injuries have been limited. We reported a novel strategy by applying MSC-EVs boosted with bioactive glasses (BG). BG-elicited EVs (EV_B) showed up-regulation of medicinal miRNAs, including miR-199b-3p and miR-125a-5p, which play a pivotal role in M2 Mφ-mediated angiogenesis. EV_B accelerated angiogenesis via the reprogrammed anti-inflammatory M2 Mφs compared with naïve MSC-EVs (EV_N). In rodent Achilles tendon rupture model, EV_B local administration activated anti-inflammatory responses via M2 polarization and led to a spatial correlation between M2 Mφs and newly formed blood vessels. Our results showed that EV_B outperformed EV_N in promoting tenogenesis and in reducing detrimental morphological changes without causing heterotopic ossification. Biomechanical test revealed that EV_B significantly improved ultimate load, stiffness, and tensile modulus of the repaired tendon, along with a positive correlation between M2/M1 ratio and biomechanical properties. On the basis of the boosted nature to reprogram regenerative microenvironment, EV_B holds considerable potential to be developed as a next-generation therapeutic modality for enhancing functional regeneration to achieve satisfying tendon regeneration.

Keywords: Angiogenesis; Bioactive glass; Extracellular vesicles; Macrophage; MicroRNAs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Extracellular Vesicles*
Humans
Macrophages
Mesenchymal Stem Cells* / physiology
MicroRNAs*
Tendon Injuries* / therapy
Tendons

Substances

MicroRNAs