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

Stem Cell Research & Therapy

Research

Andre J. van Wijnen¹  Roman Thaler²  Samer H. Barsom³  Kyra L. Jordan³  Sarosh Siddiqi³  Kamalnath Sankaran Rajagopalan³  Xiang-Yang Zhu³  Alfonso Eirin³  Mohit Mirchandani³  Tomiwa S. Oderinde³  Logan M. Glasstetter³  Ishran M. Saadiq³  Lilach O. Lerman³  Hui Tang³ 

[1] Department of Biochemistry, University of Vermont, Burlington, VT, USA;Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA;Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, 55905, Rochester, MN, USA;

关键词: Mesenchymal stem/stromal cells;    Epigenetics;    Hydroxymethylation;    Apoptosis;    Senescence;    Obesity;    Vitamin-C;   

DOI  :  10.1186/s13287-023-03372-x

 received in 2022-06-16, accepted in 2023-05-09,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundObesity 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.MethodsFemale 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.ResultshMeDIP-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.ConclusionsObesity 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.

【 授权许可】

CC BY   
© The Author(s) 2023

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