Combination of resveratrol and 5-azacytydine improves osteogenesis of metabolic syndrome mesenchymal stem cells.
Abstract: Endocrine disorders have become more and more frequently diagnosed in humans and animals. In horses, equine metabolic syndrome (EMS) is characterized by insulin resistance, hyperleptinemia, hyperinsulinemia, inflammation and usually by pathological obesity. Due to an increased inflammatory response in the adipose tissue, cytophysiological properties of adipose derived stem cells (ASC) have been impaired, which strongly limits their therapeutic potential. Excessive accumulation of reactive oxygen species, mitochondria deterioration and accelerated ageing of those cells affect their multipotency and restrict the effectiveness of the differentiation process. In the present study, we have treated ASC isolated from EMS individuals with a combination of 5-azacytydine (AZA) and resveratrol (RES) in order to reverse their aged phenotype and enhance osteogenic differentiation. Using SEM and confocal microscope, cell morphology, matrix mineralization and mitochondrial dynamics were assessed. Furthermore, we investigated the expression of osteogenic-related genes with RT-PCR. We also investigated the role of autophagy during differentiation and silenced PARKIN expression with siRNA. Obtained results indicated that AZA/RES significantly enhanced early osteogenesis of ASC derived from EMS animals. Increased matrix mineralization, RUNX-2, collagen type I and osteopontin levels were noted. Furthermore, we proved that AZA/RES exerts its beneficial effects by modulating autophagy and mitochondrial dynamics through PARKIN and RUNX-2 activity.
© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
Publication Date: 2018-07-12 PubMed ID: 29999247PubMed Central: PMC6156237DOI: 10.1111/jcmm.13731Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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This research investigates the combined effect of two substances, 5-azacytydine (AZA) and resveratrol (RES), on improving bone formation in the stem cells derived from individuals with an equine metabolic syndrome (EMS), a condition prevalent in horses that resembles human metabolic disorders.
Background
- Equine metabolic syndrome (EMS) in horses is an endocrine disorder that mirrors similar metabolic conditions in humans, characterized by insulin resistance, elevated levels of leptin and insulin, inflammation, and often pathological obesity.
- Adipose derived stem cells (ASC) suffer from impaired physiological properties due to increased inflammation in adipose tissue prevalent in EMS which compromises their therapeutic potential.
- Factors such as excessive reactive oxygen species, mitochondrial degradation, and expedited aging of these cells compromise their multipotency and limit the differentiation process’s effectiveness.
Objectives
- The study aimed to determine whether treating ASC derived from EMS individuals with a combination of 5-azacytydine (AZA) and resveratrol (RES) can reverse their aged phenotype and enhance osteogenic or bone cell differentiation.
Methods
- Cell morphology, matrix mineralization, and mitochondrial dynamics were observed using SEM and confocal microscopes after treating ASC cells derived from EMS animals with AZA/RES.
- Gene expression related to osteogenesis (bone formation) was studied using RT-PCR.
- The role of autophagy (cellular self-degradation process) during differentiation was examined and PARKIN expression, which plays a role in regulating mitochondria’s activity, was silenced with siRNA.
Results
- It was found that the combined treatment with AZA/RES significantly enhanced early osteogenesis in stem cells derived from EMS animals.
- Increased matrix mineralization, RUNX-2, collagen type I, and osteopontin levels were noted in the treated cells suggesting successful bone formation.
- It was also found that AZA/RES exerts its beneficial effects by modulating autophagy and mitochondrial dynamics through the activity of PARKIN and RUNX-2 genes.
Cite This Article
APA
Marycz K, Kornicka K, Irwin-Houston JM, Weiss C.
(2018).
Combination of resveratrol and 5-azacytydine improves osteogenesis of metabolic syndrome mesenchymal stem cells.
J Cell Mol Med, 22(10), 4771-4793.
https://doi.org/10.1111/jcmm.13731 Publication
Researcher Affiliations
- Department of Experimental Biology, Wroclaw University of Environmental and Life Sciences, Wroclaw, Poland.
- Wroclaw Research Centre EIT+, Wrocław, Poland.
- Department of Experimental Biology, Wroclaw University of Environmental and Life Sciences, Wroclaw, Poland.
- PferdePraxis Dr. Med. Vet. Daniel Weiss, Freienbach, Switzerland.
- PferdePraxis Dr. Med. Vet. Daniel Weiss, Freienbach, Switzerland.
MeSH Terms
- Adipose Tissue / drug effects
- Adipose Tissue / metabolism
- Adipose Tissue / pathology
- Animals
- Autophagy / drug effects
- Autophagy / genetics
- Azacitidine / pharmacology
- Cell Differentiation / drug effects
- Cellular Senescence / drug effects
- Collagen Type I / agonists
- Collagen Type I / genetics
- Collagen Type I / metabolism
- Core Binding Factor Alpha 1 Subunit / agonists
- Core Binding Factor Alpha 1 Subunit / genetics
- Core Binding Factor Alpha 1 Subunit / metabolism
- Drug Combinations
- Female
- Gene Expression Regulation
- Horse Diseases / drug therapy
- Horse Diseases / genetics
- Horse Diseases / pathology
- Horses
- Insulin Resistance
- Male
- Mesenchymal Stem Cells / drug effects
- Mesenchymal Stem Cells / metabolism
- Mesenchymal Stem Cells / pathology
- Metabolic Syndrome / drug therapy
- Metabolic Syndrome / genetics
- Metabolic Syndrome / pathology
- Metabolic Syndrome / veterinary
- Mitochondrial Dynamics / drug effects
- Obesity / drug therapy
- Obesity / genetics
- Obesity / pathology
- Obesity / veterinary
- Osteoblasts / cytology
- Osteoblasts / drug effects
- Osteoblasts / metabolism
- Osteogenesis / drug effects
- Osteogenesis / genetics
- Osteopontin / agonists
- Osteopontin / genetics
- Osteopontin / metabolism
- Oxidative Stress
- RNA, Small Interfering / genetics
- RNA, Small Interfering / metabolism
- Reactive Oxygen Species / antagonists & inhibitors
- Reactive Oxygen Species / metabolism
- Resveratrol / pharmacology
- Signal Transduction
- Ubiquitin-Protein Ligases / antagonists & inhibitors
- Ubiquitin-Protein Ligases / genetics
- Ubiquitin-Protein Ligases / metabolism
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