Apoptotic vesicles restore liver macrophage homeostasis to counteract type 2 diabetes

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.

Mesenchymal stromal cell apoptosis is required for their therapeutic function

“…extracellular vesicles) offer an attractive cell-free therapeutic alternative, they may not be a direct measure of potency when viable MSCs are infused as a cellular product. On the other hand, apoptotic MSC-derived extracellular vesicles have recently been shown to demonstrate therapeutic potential 47 , 69 – 71 . Our data provide further understanding of the mechanisms of MSC therapy and reveal opportunities for novel therapeutic interventions.…”

Sympathetic Neurostress Drives Osteoblastic Exosomal MiR‐21 Transfer to Disrupt Bone Homeostasis and Promote Osteopenia

“…[ 33 ] Transmission electron microscopy (TEM) was performed on whole mounts of isolated exosomes deposited on copper mesh, stained with phosphotungstic acid at room temperature for 30 s, washed with distilled water for 10 s and dried prior to imaging with a TEM (JEM‐1230, JEOL, Japan). [ 65 ] Quantification of exosomes was performed by determining the concentration of total proteins using the Pierce BCA Protein Assay (23225, Thermo Fisher Scientific, USA). Labeling of exosomes was performed using PKH26 according to the manufacturer's protocol (MINI26, Sigma Aldrich, USA).…”

Utility of extracellular vesicles as a potential biological indicator of physiological resilience during military operational stress

“…However, when the apoptosis‐deficient mice were infused with exogenous apoptotic bodies weekly for 4 weeks, mesenchymal cells were restored and the osteopenia phenotype was mitigated (Liu et al, 2018b ). Similarly, apoptotic bodies were shown to functionally modulate liver macrophage homeostasis to counteract Type 2 diabetes, improving glucose tolerance and insulin sensitivity (Zheng et al, 2021 ). Apoptotic bodies are enveloped and ingested by macrophages, dendritic cells, and endothelial cells, then degraded by lysosomes (Liu et al, 2018b ).…”