Obesity-driven mitochondrial dysfunction in human adipose tissue-derived mesenchymal stem/stromal cells involves...

Area of Science:

• Epigenetics
• Mitochondrial Biology
• Stem Cell Biology

Background:

• Obesity negatively impacts mesenchymal stem/stromal cell (MSC) function and tissue repair.
• Mitochondria play a crucial role in MSC viability, proliferation, and differentiation.
• Mechanisms underlying obesity-induced MSC dysfunction remain unclear.

Purpose of the Study:

• To investigate if epigenetic alterations in mitochondria-related genes mediate obesity-driven dysfunction in human adipose-derived MSCs.
• To explore the impact of obesity on the 5-hydroxymethylcytosine (5hmC) profile of mitochondrial genes in MSCs.
• To assess the functional consequences of these epigenetic changes on MSCs.

Main Methods:

• Harvested MSCs from obese and non-obese subjects.
• Utilized hydroxymethylated DNA immunoprecipitation sequencing (hMeDIP-seq) and mRNA sequencing (mRNA-seq) to analyze 5hmC profiles and gene expression.
• Evaluated MSC mitochondrial structure, function, metabolomics, proliferation, and neurogenic differentiation in vitro.
• Assessed effects of epigenetic modulation on MSCs.

Main Results:

• Obesity altered 5hmC profiles in nuclear-encoded mitochondrial genes (99 hyper, 150 hypo).
• Integrated analysis revealed overlapping changes in 5hmC and mRNA for genes involved in ATP production, redox, proliferation, and metabolism.
• Obese-MSCs showed impaired mitochondrial function, reduced fatty acid metabolism, and decreased neurogenic differentiation, which were improved by epigenetic modulation.

Conclusions:

• Obesity induces epigenetic modifications in mitochondria-related genes within human adipose-derived MSCs.
• These epigenetic changes correlate with mitochondrial structural/functional deficits and impaired MSC regenerative capacity.
• Findings suggest potential therapeutic targets for enhancing MSC function in obesity.