Obesity and dyslipidemia are associated with partially reversible modifications to DNA hydroxymethylation of apoptosis- and senescence-related genes in swine adipose-derived mesenchymal stem/stromal cells

Obesity dysregulates key biological processes underlying the functional homeostasis, fate decisions, and reparative potential of mesenchymal stem/stromal cells (MSCs). Mechanisms directing obesity-induced phenotypic alterations in MSCs remain unclear, but emerging drivers include dynamic modificatio...

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Published in:	Stem cell research & therapy Vol. 14; no. 1; p. 143
Main Authors:	Glasstetter, Logan M, Oderinde, Tomiwa S, Mirchandani, Mohit, Rajagopalan, Kamalnath Sankaran, Barsom, Samer H, Thaler, Roman, Siddiqi, Sarosh, Zhu, Xiang-Yang, Tang, Hui, Jordan, Kyra L, Saadiq, Ishran M, van Wijnen, Andre J, Eirin, Alfonso, Lerman, Lilach O
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 25-05-2023 BioMed Central BMC
Subjects:	Abdomen Adipose tissue Adipose tissues Animals Antibodies Anticoagulants Apoptosis Apoptosis - genetics Blood pressure Body fat Body mass index Cardiovascular diseases Cell proliferation Cellular Senescence - genetics Chronic illnesses Deoxyribonucleic acid Disease DNA DNA sequencing Domestic animals Dyslipidemia Dyslipidemias - genetics Enzymes Epigenetic inheritance Epigenetics Female Gene set enrichment analysis Genes Genetic research Genomes Glucose Hogs Homeostasis Humans Hydroxymethylation Immunoprecipitation Immunoreactivity Insulin resistance Mesenchymal stem/stromal cells Metabolic disorders mRNA Nutrition research Obesity Obesity - genetics Obesity - metabolism Proteins Risk factors RNA RNA sequencing RNA, Messenger Senescence Stem cells Stromal cells Stromal Cells - metabolism Sus scrofa Swine Transplantation Transplants & implants Triglycerides Vitamins β-Galactosidase Obesity Senescence Epigenetics Hydroxymethylation Vitamin-C Apoptosis Mesenchymal stem/stromal cells
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Summary:	Obesity dysregulates key biological processes underlying the functional homeostasis, fate decisions, and reparative potential of mesenchymal stem/stromal cells (MSCs). Mechanisms directing obesity-induced phenotypic alterations in MSCs remain unclear, but emerging drivers include dynamic modification of epigenetic marks, like 5-hydroxymethylcytosine (5hmC). We hypothesized that obesity and cardiovascular risk factors induce functionally relevant, locus-specific changes in 5hmC of swine adipose-derived MSCs and evaluated their reversibility using an epigenetic modulator, vitamin-C. Female domestic pigs were fed a 16-week Lean or Obese diet (n = 6 each). MSCs were harvested from subcutaneous adipose tissue, and 5hmC profiles were examined through hydroxymethylated DNA immunoprecipitation sequencing (hMeDIP-seq) followed by an integrative (hMeDIP and mRNA sequencing) gene set enrichment analysis. For clinical context, we compared 5hmC profiles of adipose tissue-derived human MSCs harvested from patients with obesity and healthy controls. hMeDIP-seq revealed 467 hyper- (fold change ≥ 1.4; p-value ≤ 0.05) and 591 hypo- (fold change ≤ 0.7; p-value ≤ 0.05) hydroxymethylated loci in swine Obese- versus Lean-MSCs. Integrative hMeDIP-seq/mRNA-seq analysis identified overlapping dysregulated gene sets and discrete differentially hydroxymethylated loci with functions related to apoptosis, cell proliferation, and senescence. These 5hmC changes were associated with increased senescence in cultured MSCs (p16/CDKN2A immunoreactivity, senescence-associated β-galactosidase [SA-β-Gal] staining), were partly reversed in swine Obese-MSCs treated with vitamin-C, and shared common pathways with 5hmC changes in human Obese-MSCs. Obesity and dyslipidemia are associated with dysregulated DNA hydroxymethylation of apoptosis- and senescence-related genes in swine and human MSCs, potentially affecting cell vitality and regenerative functions. Vitamin-C may mediate reprogramming of this altered epigenomic landscape, providing a potential strategy to improve the success of autologous MSC transplantation in obese patients.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1757-6512 1757-6512
DOI:	10.1186/s13287-023-03372-x