Transmissible Endoplasmic Reticulum Stress Mediated by Extracellular Vesicles from Adipocyte Promoting the Senescence of Adipose-Derived Mesenchymal Stem Cells in Hypertrophic Obesity

Abstract

Hypertrophic obesity, characterized by an excessive expansion of subcutaneous adipocytes, causes chronic inflammation and insulin resistance. It is the primary feature of obesity in middle-aged and elderly individuals. In the adipose microenvironment, a high level of endoplasmic reticulum (ER) stress and changes in the extracellular vesicle (EV) composition of adipocytes may cause the senescence and restrained differentiation of progenitor cells of adipose, including adipose-derived mesenchymal stem cells (ASCs). In this study, a hypertrophic obesity mouse model was established, and the effects of adipocytes on the ER stress and senescence of ASCs were observed in a coculture of control ASCs and hypertrophic obesity mouse adipocytes or their derived EVs. The adipocytes of hypertrophic obesity mice were treated with GW4869 or an iron chelation agent to observe the effects of EVs secreted by adipocytes and their iron contents on the ER stress and senescence of ASCs. Results showed higher ER stress level and senescence phenotypes in the ASCs from the hypertrophic obesity mice than in those from the control mice. The ER stress, senescence phenotypes, and ferritin level of ASCs can be aggravated by the coculture of ASCs with adipocytes or EVs released by them from the hypertrophic obesity mice. GW4869 or iron chelator treatment improved the ER stress and senescence of the ASCs cocultured with EVs released by the adipocytes of the hypertrophic obesity mice. Our findings suggest that EV-mediated transmissible ER stress is responsible for the senescence of ASCs in hypertrophic obesity mice.

Inhibition of MiR‐106b‐5p mediated by exosomes mitigates acute kidney injury by modulating transmissible endoplasmic reticulum stress and M1 macrophage polarization

“…17 Moreover, shreds of evidence suggest that the transmissible ER stress is capable of afflicting phenotypic and functional alterations in neighbouring cells, depending largely on the pathophysiological context that triggers endoplasmic reticulum stress activation in donor cells, as well as on the specific cell type undergoing this process. [18][19][20] Exosomes are crucial mediators to exert paracrine effects and can functionally regulate neighbouring or distant recipient cells. 5,21 Heusermann et al 22 indicated that the endoplasmic reticulum of recipient cells might be the principal site of exosome cargo release, as approximately 90% of exosomes have been shown to stagnate at or near the ER.…”

“…In addition to nutritional deficiency, renal tubular epithelial cells are susceptible to hypoxia 17 . Moreover, shreds of evidence suggest that the transmissible ER stress is capable of afflicting phenotypic and functional alterations in neighbouring cells, depending largely on the pathophysiological context that triggers endoplasmic reticulum stress activation in donor cells, as well as on the specific cell type undergoing this process 18–20 …”

Fat Biology in Triple-Negative Breast Cancer: Immune Regulation, Fibrosis, and Senescence

“…Furthermore, there is a noticeable connection between the functional aspects of invasion, migration, and ER stress in TNBC. 97,98 Evidence is emerging to suggest that various cellular stresses associated with obesity and tumors play a role in cellular senescence, resulting in accumulation of senescent cells in adipose tissue and various types of cancer.…”

Obese visceral fat tissue inflammation: from protective to detrimental?

“…Senescent cells positively impact health span, liver, and vascular tissue fibrosis, and wound healing [119,120]. However, if senescent cells are not cleared within days or weeks by innate immune cells, they accumulate and spread senescence to neighboring and distant cells, mostly via secretion of microRNA-containing vesicles with the consequence of a pro-fibrotic state and deficient tissue function in hypertrophic obesity mice [46,[121][122][123]. Obesity and hyperinsulinemia also drive the senescence of adipocytes or visceral fat macrophages in humans [91,124].…”