Exosomal PD-L1 induces osteogenic differentiation and promotes fracture healing by acting as an immunosuppressant.

Abstract

A moderate inflammatory response at the early stages of fracture healing is necessary for callus formation. Over-active and continuous inflammation, however, impairs fracture healing and leads to excessive tissue damage. Adequate fracture healing could be promoted through suppression of local over-active immune cells in the fracture site. In the present study, we achieved an enriched concentration of PD-L1 from exosomes (Exos) of a genetically engineered Human Umbilical Vein Endothelial Cell (HUVECs), and demonstrated that exosomes overexpressing PD-L1 specifically bind to PD-1 on the T cell surface, suppressing the activation of T cells. Furthermore, exosomal PD-L1 induced Mesenchymal Stem Cells (MSCs) towards osteogenic differentiation when pre-cultured with T cells. Moreover, embedding of Exos into an injectable hydrogel allowed Exos delivery to the surrounding microenvironment in a time-released manner. Additionally, exosomal PD-L1, embedded in a hydrogel, markedly promoted callus formation and fracture healing in a murine model at the early over-active inflammation phase. Importantly, our results suggested that activation of T cells in the peripheral lymphatic tissues was inhibited after local administration of PD-L1-enriched Exos to the fracture sites, while T cells in distant immune organs such as the spleen were not affected. In summary, this study provides the first example of using PD-L1-enriched Exos for bone fracture repair, and highlights the potential of Hydrogel@Exos systems for bone fracture therapy through immune inhibitory effects.

• Authors: Ze Lin, Yuan Xiong, Weilin Meng, Yiqiang Hu, Lili Chen, Lang Chen, Hang Xue, Adriana C Panayi, Wu Zhou, Yun Sun, Faqi Cao, Guodong Liu, Liangcong Hu, Chenchen Yan, Xudong Xie, Chuanchuan Lin, Kaiyong Cai, Qian Feng, Bobin Mi, Guohui Liu
• Journal: Bioactive materials (Bioact Mater) Vol. 13 Pg. 300-311 (Jul 2022) ISSN: 2452-199X [Electronic] China
• PMID: 35224310 (Publication Type: Journal Article)
• Copyright: © 2021 The Authors.