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H3K9ac ChIP-seq profiling of wild-type and Slc31a1 conditional knockout mouse bone marrow stromal cells

ABSTRACT: Age-associated bone loss is largely driven by impaired osteoblast generation from bone marrow stromal cells (BMSCs), but the metabolic and epigenetic mechanisms that regulate osteogenic commitment remain incompletely understood. This study identifies SLC31A1-mediated copper uptake as a cell-intrinsic metabolic checkpoint required for BMSC osteogenic differentiation and skeletal integrity. Mesenchymal lineage-specific Slc31a1 deletion impaired bone formation and BMSC osteogenesis and caused Slc31a1-deficient BMSCs to accumulate in an ID1-high progenitor-like state. To investigate the epigenetic mechanism underlying this phenotype, H3K9ac ChIP-seq was performed in wild-type and Slc31a1 conditional knockout mouse BMSCs. The analysis revealed increased H3K9ac enrichment in Slc31a1-deficient BMSCs, including enhanced H3K9ac signal at the Id1 locus, supporting a model in which SLC31A1-dependent copper uptake maintains mitochondrial complex IV integrity and NAD+ homeostasis to enable SIRT1-dependent epigenetic repression of Id1 during osteogenic commitment.

ORGANISM(S): Mus musculus

PROVIDER: GSE337269 | GEO | 2026/07/31

REPOSITORIES: GEO

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Project description:The treatment of bone defects caused by infection, trauma or neoplasms remains a clinical challenge. Autologous bone transplantation is limited by availability, donor site morbidity and surgical risk factors. This has given rise to stromal/stem-cell based therapy. Bone marrow derived stromal cells (BMSCs) have been studied to a large extent and show high regenerative potential but their use is limited by availability, donor site morbidity and the relatively low cell yield as they represent only <0.1% of cell harvested from bone marrow aspirate. At the same time, they are the closest mesenchymal stromal cells for bone tissue engineering given their tissue origin and, unlike other mesenchymal stromal cells, can support the formation of hematopoietic marrow. Adipose tissue derived stromal cells (ASCs) as part of the stromal vascular fraction of adipose tissue can as well undergo osteogenic differentiation but can be additionally isolated in a sufficient quantity from lipoaspirate after liposuction of abundant subcutaneous fat tissue. Here, it has been shown that there are no major differences in regard to proliferation or differentiation capacity of ASCs derived from subcutaneous fat of different anatomical regions. It has been shown that BMSCs are more prone to senescence during expansion and passage than ASCs and that ageing impacts proliferative capabilities of BMSCs more than that of ASCs while it has also been reported that osteogenic differentiation capacity is least impacted by age. Multiple studies have compared the characteristics of these two mesenchymal stromal cells in regard to bone tissue engineering in vitro. Most studies point to inferior extracellular matrix mineralization and lower expression of key osteogenic transcription markers like Runx2 in osteogenic differentiated ASCs compared to BMSCs. On the other hand, a study by Rath et al. found contrary results using particular culturing conditions like 3D bioglass scaffolds. An intraindividual comparison of human MSCs of three donors cultured on decellularized porcine bone confirmed superior osteogenic capacity of BMSCs compared to ASCs. In contrast to BMSCs, ASCs were not able to induce heterogenic ossification in a mouse model. In a sheep tibia defect model application of BMSCs resulted in a significantly higher amount of newly formed bone tissue. Importantly, Osteogenic differentiated ASCs do not support the formation of a hematopoietic marrow. Proteomics enables large-scale analysis of proteins present in a cell type and can be used to identify differentially regulated key proteins in a comparative approach. A comparative proteomic analysis of BMSCs and ASCs by Roche et al. in 2009 identified 556 proteins with 78% of these not being differentially regulated between these two cell populations, regarded as high similarity. Another comparative proteomic study of 2016 by Jeon et al. found 90 differentially regulated proteins out of 3000 total identified proteins. Both studies do not specify a number of different tissue donors and in part using cell lines. Looking for differences upon osteogenic differentiation, transcriptomic comparison of osteogenic differentiated porcine ASCs and BMSCs has been performed, resulting in 21 differentially expressed genes after 21 days of osteogenic culture conditions. Still, it remains unanswered, which are the key distinctive features of osteogenic differentiated ASCs and BMSCs at protein level that might help address the abovementioned weaknesses of ASCs in bone tissue engineering/regeneration for translational research. To overcome this need, an intraindividual comparative DIA based proteomic analysis of osteogenic differentiated human BMSC and ASCs was performed in this study.

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H3K9ac ChIP-seq profiling of wild-type and Slc31a1 conditional knockout mouse bone marrow stromal cells

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