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Studies have utilized transcriptomics data to link disease\u2010associated variants to genes, but few population transcriptomics data sets have been generated on bone at the single\u2010cell level. To address this challenge, we profiled the transcriptomes of bone marrow\u2013derived stromal cells (BMSCs) cultured under osteogenic conditions from five diversity outbred (DO) mice using single\u2010cell RNA\u2010seq (scRNA\u2010seq). The goal of the study was to determine if BMSCs could serve as a model to generate cell type\u2013specific transcriptomic profiles of mesenchymal lineage cells from large populations of mice to inform genetic studies. By enriching for mesenchymal lineage cells in vitro, coupled with pooling of multiple samples and downstream genotype deconvolution, we demonstrate the scalability of this model for population\u2010level studies. We demonstrate that dissociation of BMSCs from a heavily mineralized matrix had little effect on viability or their transcriptomic signatures. Furthermore, we show that BMSCs cultured under osteogenic conditions are diverse and consist of cells with characteristics of mesenchymal progenitors, marrow adipogenic lineage precursors (MALPs), osteoblasts, osteocyte\u2010like cells, and immune cells. Importantly, all cells were similar from a transcriptomic perspective to cells isolated in vivo. We employed scRNA\u2010seq analytical tools to confirm the biological identity of profiled cell types. SCENIC was used to reconstruct gene regulatory networks (GRNs), and we observed that cell types show GRNs expected of osteogenic and pre\u2010adipogenic lineage cells. Further, CELLECT analysis showed that osteoblasts, osteocyte\u2010like cells, and MALPs captured a significant component of bone mineral density (BMD) heritability. Together, these data suggest that BMSCs cultured under osteogenic conditions coupled with scRNA\u2010seq can be used as a scalable and biologically informative model to generate cell type\u2013specific transcriptomic profiles of mesenchymal lineage cells in large populations. \u00a9 2023 The Authors. <jats:italic>Journal of Bone and Mineral Research<\/jats:italic> published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).<\/jats:p>","DOI":"10.1002\/jbmr.4882","type":"journal-article","created":{"date-parts":[[2023,7,12]],"date-time":"2023-07-12T12:59:36Z","timestamp":1689166776000},"page":"1350-1363","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Single\u2010Cell Transcriptomics of Bone Marrow Stromal Cells in Diversity Outbred Mice: A Model for Population\u2010Level <scp>scRNA<\/scp>\u2010Seq Studies"],"prefix":"10.1093","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8293-0479","authenticated-orcid":false,"given":"Luke J","family":"Dillard","sequence":"first","affiliation":[{"name":"Center for Public Health Genomics, School of Medicine University of Virginia  Charlottesville VA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Will T","family":"Rosenow","sequence":"additional","affiliation":[{"name":"Center for Public Health Genomics, School of Medicine University of Virginia  Charlottesville VA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gina M","family":"Calabrese","sequence":"additional","affiliation":[{"name":"Center for Public Health Genomics, School of Medicine University of Virginia  Charlottesville VA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Larry D","family":"Mesner","sequence":"additional","affiliation":[{"name":"Center for Public Health Genomics, School of Medicine 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