Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
Cell Death Dis. 2024 Jun 1;15(6):387. doi: 10.1038/s41419-024-06774-8.
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.
肥胖加剧了组织退化，并损害了间充质干细胞（MSCs）的完整性和修复潜能，但潜在机制尚未得到充分阐明。线粒体调节 MSCs 的活力、可塑性、增殖能力和分化潜能。我们假设，线粒体相关基因的 5-羟甲基胞嘧啶（5hmC）谱的改变可能介导肥胖驱动的人脂肪来源 MSCs 功能障碍。从肥胖和年龄/性别匹配的非肥胖受试者的腹部皮下脂肪中采集 MSCs（每组各 5 例）。通过羟甲基化 DNA 免疫沉淀测序（h MeDIP-seq）和 mRNA-seq 分别检测 5hmC 谱和核编码线粒体基因的表达。在体外评估 MSC 线粒体结构（电子显微镜）和功能、代谢组学、增殖和神经发生分化，然后进行表观遗传调节。hMeDIP-seq 确定了与非肥胖对照相比，肥胖对照 MSC 中核编码线粒体基因的 99 个高羟甲基化峰和 150 个低羟甲基化峰。综合 hMeDIP-seq/mRNA-seq 分析确定了一组重叠的核编码线粒体基因（5hmC 和 mRNA 水平均改变），这些基因参与 ATP 产生、氧化还原活性、细胞增殖、迁移、脂肪酸代谢和神经元发育。此外，肥胖对照 MSC 表现出线粒体基质密度、膜电位和脂肪酸代谢物水平降低，超氧化物产生增加，神经发生分化受损，这些表型可通过表观遗传调节得到改善。肥胖引起人脂肪来源 MSCs 中线粒体相关基因的表观遗传变化，伴随着其线粒体的结构和功能变化，以及脂肪酸代谢和神经发生分化能力受损。这些观察结果可能有助于开发新的疗法，以保持肥胖个体中 MSC 用于组织修复和再生的潜能。
