期刊
JOURNAL OF EXTRACELLULAR VESICLES
卷 10, 期 7, 页码 -出版社
WILEY
DOI: 10.1002/jev2.12109
关键词
apoptotic vesicles; calreticulin; efferocytosis; macrophages; mesenchymal stem cells; type 2 diabetes
类别
资金
- National Key Research and Development Program of China [2016YFC1101400]
- National Natural Science Foundation of China [32000974, 31800817, 81670915, 31870970]
- Postdoctoral Innovative Talents Support Program of China [BX20190380]
- General Program of China Postdoctoral Science Foundation [2019M663986]
- Guangdong Financial Fund for High-Caliber Hospital Construction [174-2018-XMZC-000103-0125]
- Pearl River Talent Recruitment Program [2019ZT08Y485]
- National Science and Technology Major Project of the Ministry of Science and Technology of China [2018ZX10302207-001-002]
- Innovative Talent Project of Shaanxi province [2020KJXX-057]
The study revealed that apoptotic vesicles (apoVs) derived from MSCs can modulate liver macrophage homeostasis and counteract type 2 diabetes (T2D) by inducing macrophage reprogramming. Through efferocytosis, apoVs inhibit macrophage accumulation and promote their transformation towards an anti-inflammatory phenotype in the liver to ameliorate T2D phenotypes.
Apoptosis is a naturally occurring process generating plenty of apoptotic vesicles (apoVs), but the feature, fate and function of apoVs remain largely unknown. Notably, as an appealing source for cell therapy, mesenchymal stem cells (MSCs) undergo necessary apoptosis and release apoVs during therapeutic application. In this study, we characterized and used MSC-derived apoVs to treat type 2 diabetes (T2D) mice, and we found that apoVs were efferocytosed by macrophages and functionally modulated liver macrophage homeostasis to counteract T2D. We showed that apoVs can induce macrophage reprogramming at the transcription level in an efferocytosis-dependent manner, leading to inhibition of macrophage accumulation and transformation of macrophages towards an anti-inflammation phenotype in T2D liver. At the molecular level, we discovered that calreticulin (CRT) was exposed on the surface of apoVs to act as a critical 'eat-me' signal mediating apoV efferocytosis and macrophage regulatory effects. Importantly, we demonstrated that CRT-mediated efferocytosis of MSC-derived apoVs contributes to T2D therapy with alleviation of T2D phenotypes including glucose intolerance and insulin resistance. These findings uncover that functional efferocytosis of apoVs restores liver macrophage homeostasis and ameliorates T2D.
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