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Updated: Nov 3, 2025
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Published on: April 3, 2017
Apoptotic vesicles restore liver macrophage homeostasis to counteract type 2 diabetes
Chenxi Zheng1, Bingdong Sui1,2, Xiao Zhang3,2
1State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases Center for Tissue Engineering School of Stomatology The Fourth Military Medical University Xi'an Shaanxi China.
Abstract:
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.
Insights
Mesenchymal stem cell-derived apoptotic vesicles (apoVs) reprogram liver macrophages to combat type 2 diabetes. Calreticulin on apoVs mediates their uptake by macrophages, restoring immune balance and improving diabetes symptoms.
Area of Science:
- Cell Biology
- Immunology
- Metabolic Diseases
Background:
- Apoptotic vesicles (apoVs) are abundant but their functions are poorly understood.
- Mesenchymal stem cells (MSCs) release apoVs during therapy, presenting a potential therapeutic avenue.
- Type 2 diabetes (T2D) involves complex immune dysregulation, particularly in liver macrophages.
Purpose of the Study:
- To investigate the therapeutic potential of MSC-derived apoVs in T2D.
- To elucidate the mechanism by which apoVs modulate macrophage function in T2D.
- To identify molecular mediators of apoV-macrophage interaction.
Main Methods:
- Characterization of MSC-derived apoVs.
- In vivo administration of apoVs to T2D mouse models.
- Analysis of macrophage efferocytosis and phenotype.
- Transcriptional profiling of macrophages.
- Identification of surface molecules on apoVs using molecular techniques.
Main Results:
- MSC-derived apoVs were efficiently efferocytosed by macrophages in T2D livers.
- ApoV efferocytosis reprogrammed macrophages at the transcriptional level, promoting an anti-inflammatory phenotype.
- Calreticulin (CRT) on apoV surfaces acted as an 'eat-me' signal, crucial for efferocytosis and macrophage modulation.
- CRT-mediated apoV uptake alleviated T2D phenotypes, including glucose intolerance and insulin resistance.
Conclusions:
- MSC-derived apoVs can restore liver macrophage homeostasis in T2D through efferocytosis.
- Calreticulin is a key mediator of apoV efferocytosis and its therapeutic effects.
- Functional efferocytosis of apoVs offers a novel therapeutic strategy for T2D by modulating the immune microenvironment.
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