Osteogenic Differentiation Potential of Mesenchymal Stem Cells using Single Cell Multiomic Analysis

ABSTRACT: Mesenchymal stem cells (MSC) are multipotent stem cells that can differentiate into multiple cell types, including osteoblasts, chondrocytes and adipocytes. Osteoblast differentiation is reduced during osteoporosis development, resulting in reduced bone formation. Further, MSC isolated from different donors possess distinct osteogenic capacity. In this study, we used single-cell mul-tiomic analysis to profile the transcriptome and epigenome of MSC from four healthy donors. Da-ta were obtained from ~1,300 to 1,600 cells for each donor. These cells were clustered into four groups, indicating that MSC from different donors have distinct chromatin accessible regulatory elements for regulating gene expression. To investigate the mechanism by which MSC undergo os-teogenic differentiation, we used the chromatin accessibility data from the single-cell multiome data to identify individual-specific enhancer-promoter pairs and evaluated the expression levels and activities of the transcriptional regulators. The MSC from four donors showed distinct dif-ferentiation potential into osteoblasts. MSC of donor one showed the largest average motif activi-ties, indicating that MSC from donor one was most likely to differentiate into osteoblasts. The re-sults of our validation experiments were consistent with the bioinformatics prediction. We also tested the enrichment of GWAS signals of several musculoskeletal disease traits in the patient-specific chromatin accessible regions identified in the single-cell multiome data, including osteo-porosis, osteopenia, and osteoarthritis. We found that osteoarthritis-associated variants were on-ly enriched in the regions identified from donor four. In contrast, osteoporosis and osteopenia variants were enriched in regions from donor one and least enriched in donor four. Since osteo-porosis and osteopenia are related to the density of bone cells, the enrichment of variants from these traits should be correlated with the osteogenic potential of MSC. In summary, this study provides large-scale data to link regulatory elements with their target genes to study the regula-tory relationships during the differentiation of mesenchymal stem cells and provide a deeper in-sight into the gene regulatory mechanism.

ORGANISM(S): Homo sapiens

PROVIDER: GSE255646 | GEO | 2024/02/16

REPOSITORIES: GEO