Bioprinted constructs that simulate nerve-bone crosstalk to improve microenvironment for bone repair

Tianchang Wang; Wentao Li; Yuxin Zhang; Xiang Xu; Lei Qiang; Weiqiang Miao; Xiaokun Yue; Xin Jiao; Xianhao Zhou; Zhenjiang Ma; Shuai Li; Muliang Ding; Junfeng Zhu; Chi Yang; Hui Wang; Tao Li; Xin Sun; Jinwu Wang

doi:10.1016/j.bioactmat.2023.02.013

Bioprinted constructs that simulate nerve-bone crosstalk to improve microenvironment for bone repair

Bioact Mater. 2023 Apr 21:27:377-393. doi: 10.1016/j.bioactmat.2023.02.013. eCollection 2023 Sep.

Authors

Tianchang Wang¹, Wentao Li^{2

3}, Yuxin Zhang⁴, Xiang Xu¹, Lei Qiang⁵, Weiqiang Miao¹, Xiaokun Yue¹, Xin Jiao¹, Xianhao Zhou¹, Zhenjiang Ma¹, Shuai Li⁶, Muliang Ding⁷, Junfeng Zhu⁸, Chi Yang⁴, Hui Wang⁹, Tao Li⁸, Xin Sun¹, Jinwu Wang^{1

9}

Affiliations

¹ Shanghai Key Laboratory of Orthopedic Implant, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639 Zhizaoju Road, Shanghai, 200011, China.
² Sports Medicine Department, Beijing Key Laboratory of Sports Injuries, Peking University Third Hospital, No.49, North Garden Road, Haidian District, Beijing, 100191, China.
³ Peking University Institute of Sports Medicine, No.49, North Garden Road, Haidian District, Beijing, 100191, China.
⁴ Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, 200011, China.
⁵ School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China.
⁶ Department of Orthopedics, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd, Hangzhou, 310003, China.
⁷ Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, 410001, Hunan, China.
⁸ Department of Orthopedic Surgery, Xin Hua Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, No. 1665, Kongjiang Road, Shanghai, 200092, China.
⁹ Institute of Rehabilitation Medicine, School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Engineering Research Center of Traditional Chinese Medicine Intelligent Rehabilitation, Ministry of Education, Shanghai, 201210, China.

Abstract

Crosstalk between nerves and bone is essential for bone repair, for which Schwann cells (SCs) are crucial in the regulation of the microenvironment. Considering that exosomes are critical paracrine mediators for intercellular communication that exert important effects in tissue repair, the aim of this study is to confirm the function and molecular mechanisms of Schwann cell-derived exosomes (SC-exos) on bone regeneration and to propose engineered constructs that simulate SC-mediated nerve-bone crosstalk. SCs promoted the proliferation and differentiation of bone marrow mesenchymal stem cells (BMSCs) through exosomes. Subsequent molecular mechanism studies demonstrated that SC-exos promoted BMSC osteogenesis by regulating the TGF-β signaling pathway via let-7c-5p. Interestingly, SC-exos promoted the migration and tube formation performance of endothelial progenitor cells. Furthermore, the SC-exos@G/S constructs were developed by bioprinting technology that simulated SC-mediated nerve-bone crosstalk and improved the bone regeneration microenvironment by releasing SC-exos, exerting the regulatory effect of SCs in the microenvironment to promote innervation, vascularization, and osteogenesis and thus effectively improving bone repair in a cranial defect model. This study demonstrates the important role and underlying mechanism of SCs in regulating bone regeneration through SC-exos and provides a new engineered strategy for bone repair.

Keywords: Bioprinting; Exosomes; Microenvironment; Nerve–bone crosstalk; Schwann cells.