1. Macrophage-derived extracellular vesicles regulate skeletal stem/progenitor Cell lineage fate and bone deterioration in obesity
- Author
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Chen He, Chen Hu, Wen-Zhen He, Yu-Chen Sun, Yangzi Jiang, Ling Liu, Jing Hou, Kai-Xuan Chen, Yu-Rui Jiao, Mei Huang, Min Huang, Mi Yang, Qiong Lu, Jie Wei, Chao Zeng, Guang-Hua Lei, and Chang-Jun Li
- Subjects
Obesity-induced bone deterioration ,Macrophage-derived extracellular vesicles ,Skeletal stem/progenitor cells ,Cell fate ,Aptamer ,Cell-specific targeting ,Materials of engineering and construction. Mechanics of materials ,TA401-492 ,Biology (General) ,QH301-705.5 - Abstract
Obesity-induced chronic inflammation exacerbates multiple types of tissue/organ deterioration and stem cell dysfunction; however, the effects on skeletal tissue and the underlying mechanisms are still unclear. Here, we show that obesity triggers changes in the microRNA profile of macrophage-secreted extracellular vesicles, leading to a switch in skeletal stem/progenitor cell (SSPC) differentiation between osteoblasts and adipocytes and bone deterioration. Bone marrow macrophage (BMM)-secreted extracellular vesicles (BMM-EVs) from obese mice induced bone deterioration (decreased bone volume, bone microstructural deterioration, and increased adipocyte numbers) when administered to lean mice. Conversely, BMM-EVs from lean mice rejuvenated bone deterioration in obese recipients. We further screened the differentially expressed microRNAs in obese BMM-EVs and found that among the candidates, miR-140 (with the function of promoting adipogenesis) and miR-378a (with the function of enhancing osteogenesis) coordinately determine SSPC fate of osteogenic and adipogenic differentiation by targeting the Pparα-Abca1 axis. BMM miR-140 conditional knockout mice showed resistance to obesity-induced bone deterioration, while miR-140 overexpression in SSPCs led to low bone mass and marrow adiposity in lean mice. BMM miR-378a conditional depletion in mice led to obesity-like bone deterioration. More importantly, we used an SSPC-specific targeting aptamer to precisely deliver miR-378a-3p-overloaded BMM-EVs to SSPCs via an aptamer-engineered extracellular vesicle delivery system, and this approach rescued bone deterioration in obese mice. Thus, our study reveals the critical role of BMMs in mediating obesity-induced bone deterioration by transporting selective extracellular-vesicle microRNAs into SSPCs and controlling SSPC fate.
- Published
- 2024
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