Abstract
Obesity and endocrine disorders have become prevalent issues in the field of both human and veterinary medicine. Equine metabolic syndrome is a complex disorder involving alternation in metabolism and chronic systemic inflammation. It has been shown that unfavourable microenvironment of inflamed adipose tissue negatively affects adipose stem cell population (ASC) residing within, markedly limiting their therapeutic potential. ASCsEMS are characterized by increased senescence apoptosis, excessive accumulation of reactive oxygen species (ROS), mitochondria deterioration and “autophagic flux.” The aim of the present study was to evaluate whether treatment of ASCsEMS with a combination of 5‐azacytydine (AZA) and resveratrol (RES) would reverse aged phenotype of these cells. For this reason, we performed the following analyzes: molecular biology (RT‐PCR), microscopic (immunofluorescence, TEM) and flow cytometry (JC‐1, ROS, Ki67). We evaluated the mitochondrial status, dynamics and clearance as well as autophagic pathways. Furthermore, we investigated epigenetic alternations in treated cells by measuring the expression of TET genes and analysis of DNA methylation status. We have demonstrated that AZA/RES treatment of ASCsEMS is able to rejuvenate these cells by modulating mitochondrial dynamics, in particular by promoting mitochondrial fusion over fission. After AZA/RES treatment, ASCsEMS were characterized by increased proliferation rate, decreased apoptosis and senescence and lower ROS accumulation. Our findings offer a novel approach and potential targets for the beneficial effects of AZA/RES in ameliorating stem cell dysfunctions.
Highlights
Obesity and endocrine disorders have become common problems in the field of both human and veterinary medicine
equine metabolic syndrome (EMS) has been recognized as a factor that significantly contributes to the deterioration of adipose stem cell population (ASC) functionality
ASCsEMS were characterized by the decreased proliferation rate, increased apoptosis and senescence, mitochondrial dysfunction as well as autophagic shift – a protective mechanism maintaining their stemness status
Summary
Obesity and endocrine disorders have become common problems in the field of both human and veterinary medicine. It is estimated that approximately 19%‐40% of the horse population is obese[1] and 22%‐ 29% suffer from hyperinsulinemia.[2] Regional adiposity, obesity, hyperinsulinemia, insulin resistance (IR) and laminitis or susceptibility to laminitis are the major characteristics of equine metabolic syndrome (EMS).[3] It is worth noting that recent data have indicated that obesity should not be used as a diagnostic criterion[4] EMS is a complex disorder involving alternation in metabolism and chronic systemic inflammation.[5] due to its complexity, understanding EMS pathophysiology is still elusive. Many studies have indicated the involvement of oxidative stress in metabolic syndrome (MS). A close link between inflammation and oxidative stress plays a pivotal role in the development of IR. Strategies to treat accelerated ageing in MS should focus on modulation of mitochondrial dynamics
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