Injectable cartilage matrix hydrogel loaded with cartilage endplate stem cells engineered to release exosomes for non-invasive treatment of intervertebral disc degeneration

Liwen Luo; Junfeng Gong; Zhouguang Wang; Yao Liu; Jiaming Cao; Jinghao Qin; Rui Zuo; Hongyu Zhang; Shuai Wang; Ping Zhao; Di Yang; Mengjie Zhang; Yanqiu Wang; Junfeng Zhang; Yue Zhou; Changqing Li; Bing Ni; Zhiqiang Tian; MingHan Liu

doi:10.1016/j.bioactmat.2021.12.007

Injectable cartilage matrix hydrogel loaded with cartilage endplate stem cells engineered to release exosomes for non-invasive treatment of intervertebral disc degeneration

Bioact Mater. 2021 Dec 21:15:29-43. doi: 10.1016/j.bioactmat.2021.12.007. eCollection 2022 Sep.

Authors

Liwen Luo^{1

2}, Junfeng Gong¹, Zhouguang Wang^{3

4}, Yao Liu⁵, Jiaming Cao⁶, Jinghao Qin¹, Rui Zuo¹, Hongyu Zhang⁷, Shuai Wang⁸, Ping Zhao⁹, Di Yang², Mengjie Zhang^{10

11}, Yanqiu Wang¹, Junfeng Zhang¹², Yue Zhou¹, Changqing Li¹, Bing Ni^{10

11}, Zhiqiang Tian^{2

9}, MingHan Liu¹

Affiliations

¹ Department of Orthopaedics, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China.
² Institute of Immunology, PLA, Army Medical University (Third Military Medical University), Chongqing, China.
³ Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
⁴ Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
⁵ Department of Pharmacy, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China.
⁶ Institute of Geophysics and Geomatics, China University of Geosciences, Wuhan, China.
⁷ Department of Emergency, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
⁸ Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China.
⁹ State Key Laboratory of Silkworm Genome Biology, Biological Science Research Center, Southwest University, Chongqing, China.
¹⁰ Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University, Chongqing, China.
¹¹ Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Army Medical University (Third Military Medical University), Chongqing, China.
¹² Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, China.

Abstract

Low back pain, mainly caused by intervertebral disc degeneration (IVDD), is a common health problem; however, current surgical treatments are less than satisfactory. Thus, it is essential to develop novel non-invasive surgical methods for IVDD treatment. Here, we describe a therapeutic strategy to inhibit IVDD by injecting hydrogels modified with the extracellular matrix of costal cartilage (ECM-Gels) that are loaded with cartilage endplate stem cells (CESCs). After loaded with CESCs overexpressing Sphk2 (Lenti-Sphk2-CESCs) and injected near the cartilage endplate (CEP) of rats in vivo, ECM-Gels produced Sphk2-engineered exosomes (Lenti-Sphk2-Exos). These exosomes penetrated the annulus fibrosus (AF) and transported Sphk2 into the nucleus pulposus cells (NPCs). Sphk2 activated the phosphatidylinositol 3-kinase (PI3K)/p-AKT pathway as well as the intracellular autophagy of NPCs, ultimately ameliorating IVDD. This study provides a novel and efficient non-invasive combinational strategy for IVDD treatment using injectable ECM-Gels loaded with CESCs that express Sphk2 with sustained release of functional exosomes.

Keywords: Engineered exosomes; Extracellular matrix of costal cartilage; Hydrogels; Intervertebral disc degeneration; Sphingosine kinase 2.