Obesity-driven mitochondrial dysfunction in human adipose tissue-derived mesenchymal stem/stromal cells involves epigenetic changes.
Alfonso EirinRoman ThalerLogan M GlasstetterLi XingXiang-Yang ZhuAndrew C OsborneRonscardy MondesirAditya V BhagwateAmir LermanAndre J van WijnenLilach Orly LermanPublished in: Cell death & disease (2024)
Obesity exacerbates tissue degeneration and compromises the integrity and reparative potential of mesenchymal stem/stromal cells (MSCs), but the underlying mechanisms have not been sufficiently elucidated. Mitochondria modulate the viability, plasticity, proliferative capacity, and differentiation potential of MSCs. We hypothesized that alterations in the 5-hydroxymethylcytosine (5hmC) profile of mitochondria-related genes may mediate obesity-driven dysfunction of human adipose-derived MSCs. MSCs were harvested from abdominal subcutaneous fat of obese and age/sex-matched non-obese subjects (n = 5 each). The 5hmC profile and expression of nuclear-encoded mitochondrial genes were examined by hydroxymethylated DNA immunoprecipitation sequencing (h MeDIP-seq) and mRNA-seq, respectively. MSC mitochondrial structure (electron microscopy) and function, metabolomics, proliferation, and neurogenic differentiation were evaluated in vitro, before and after epigenetic modulation. hMeDIP-seq identified 99 peaks of hyper-hydroxymethylation and 150 peaks of hypo-hydroxymethylation in nuclear-encoded mitochondrial genes from Obese- versus Non-obese-MSCs. Integrated hMeDIP-seq/mRNA-seq analysis identified a select group of overlapping (altered levels of both 5hmC and mRNA) nuclear-encoded mitochondrial genes involved in ATP production, redox activity, cell proliferation, migration, fatty acid metabolism, and neuronal development. Furthermore, Obese-MSCs exhibited decreased mitochondrial matrix density, membrane potential, and levels of fatty acid metabolites, increased superoxide production, and impaired neuronal differentiation, which improved with epigenetic modulation. Obesity elicits epigenetic changes in mitochondria-related genes in human adipose-derived MSCs, accompanied by structural and functional changes in their mitochondria and impaired fatty acid metabolism and neurogenic differentiation capacity. These observations may assist in developing novel therapies to preserve the potential of MSCs for tissue repair and regeneration in obese individuals.
Keyphrases
- weight loss
- adipose tissue
- mesenchymal stem cells
- metabolic syndrome
- insulin resistance
- genome wide
- fatty acid
- umbilical cord
- dna methylation
- type diabetes
- oxidative stress
- single cell
- bariatric surgery
- endothelial cells
- rna seq
- stem cells
- gene expression
- bone marrow
- high fat diet
- high fat diet induced
- cell proliferation
- cell death
- induced pluripotent stem cells
- spinal cord injury
- weight gain
- obese patients
- poor prognosis
- pluripotent stem cells
- endoplasmic reticulum
- human health
- electron microscopy
- cell free
- nitric oxide
- climate change
- body mass index
- ms ms
- single molecule
- physical activity
- circulating tumor cells
- bioinformatics analysis