Full Text | PDF

Theranostics 2024; 14(9):3583-3602. doi:10.7150/thno.96174 This issue Cite

Research Paper

Extracellular vesicles from apoptotic BMSCs ameliorate osteoporosis via transporting regenerative signals

Maojiao Li¹, Qi Tang¹, Chengcheng Liao¹, Zhuo Wang¹, Siyuan Zhang¹, Qingqing Liang¹, Cheng Liang¹, Xiaodong Liu¹, Jingyi Zhang², Weidong Tian^1✉, Li Liao^1✉

1. State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Sichuan 610041, China.
2. Chengdu Shiliankangjian Biotechnology Co., Ltd., China.

✉ Corresponding author: Li Liao, Institution and address: State Key Laboratory of Oral Disease, West China School of Stomatology, Sichuan University, No. 14, 3Rd Section of Ren Min Nan Rd. Chengdu, Sichuan 610041, China. Telephone: +86-28-85503499; E-mail: lliaoedu.cn. Or Weidong Tian, Institution and address: State Key Laboratory of Oral Disease, West China School of Stomatology, Sichuan University, No. 14, 3Rd Section of Ren Min Nan Rd. Chengdu, Sichuan 610041, China. Telephone: +86-28-85501256; E-mail: drtwdcom. More

Abstract

Rationale: Mesenchymal stromal cells (MSCs) are considered a promising resource for cell therapy, exhibiting efficacy in ameliorating diverse bone diseases. However, most MSCs undergo apoptosis shortly after transplantation and produce apoptotic extracellular vesicles (ApoEVs). This study aims to clarify the potential role of ApoEVs from apoptotic MSCs in ameliorating osteoporosis and molecular mechanism.

Methods: In this study, Dio-labeled bone marrow mesenchymal stem cells (BMSCs) were injected into mice to track BMSCs apoptosis and ApoEVs production. ApoEVs were isolated from BMSCs after inducing apoptosis, the morphology, size distribution, marker proteins expression of ApoEVs were characterized. Protein mass spectrometry analysis revealed functional differences in proteins between ApoEVs and BMSCs. BMSCs were adopted to test the cellular response to ApoEVs. Ovariectomy mice were used to further compare the ability of ApoEVs in promoting bone formation. SiRNA and lentivirus were used for gain and loss-of-function assay.

Results: The results showed that BMSCs underwent apoptosis within 2 days after being injected into mice and produce a substantial quantity of ApoEVs. Proteomic analysis revealed that ApoEVs carried a diverse functional array of proteins, and easily traversed the circulation to reach the bone. After being phagocytized by endogenous BMSCs, ApoEVs efficiently promoted the proliferation, migration, and osteogenic differentiation of BMSCs. In an osteoporosis mouse model, treatment of ApoEVs alleviated bone loss and promoted bone formation. Mechanistically, ApoEVs carried Ras protein and activated the Ras/Raf1/Mek/Erk pathway to promote osteogenesis and bone formation in vitro and in vivo.

Conclusion: Given that BMSC-derived ApoEVs are high-yield and easily obtained, our data underscore the substantive role of ApoEVs from dying BMSCs to treat bone loss, presenting broad implications for cell-free therapeutic modalities.

Keywords: mesenchymal stem cell apoptosis, apoptotic cell-derived extracellular vesicles, cytotherapy, osteoporosis, Ras pathway

Citation styles

©2024 Ivyspring International Publisher. Terms of use