Dataset Information

Sox9+ messenger cells orchestrate large-scale skeletal regeneration in the mammalian rib.

ABSTRACT: Most bones in mammals display a limited capacity for natural large-scale repair. The ribs are a notable exception, yet the source of their remarkable regenerative ability remains unknown. Here, we identify a Sox9-expressing periosteal subpopulation that orchestrates large-scale regeneration of murine rib bones. Deletion of the obligate Hedgehog co-receptor, Smoothened, in Sox9-expressing cells prior to injury results in a near-complete loss of callus formation and rib bone regeneration. In contrast to its role in development, Hedgehog signaling is dispensable for the proliferative expansion of callus cells in response to injury. Instead, Sox9-positive lineage cells require Hh signaling to stimulate neighboring cells to differentiate via an unknown signal into a skeletal cell type with dual chondrocyte/osteoblast properties. This type of callus cell may be critical for bridging large bone injuries. Thus despite contributing to only a subset of callus cells, Sox9-positive progenitors play a major role in orchestrating large-scale bone regeneration. This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

SUBMITTER: Kuwahara ST

PROVIDER: S-EPMC6464605 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Sox9+ messenger cells orchestrate large-scale skeletal regeneration in the mammalian rib.

Kuwahara Stephanie T ST Serowoky Maxwell A MA Vakhshori Venus V Tripuraneni Nikita N Hegde Neel V NV Lieberman Jay R JR Crump J Gage JG Mariani Francesca V FV

eLife 20190415

Most bones in mammals display a limited capacity for natural large-scale repair. The ribs are a notable exception, yet the source of their remarkable regenerative ability remains unknown. Here, we identify a Sox9-expressing periosteal subpopulation that orchestrates large-scale regeneration of murine rib bones. Deletion of the obligate Hedgehog co-receptor, Smoothened, in Sox9-expressing cells prior to injury results in a near-complete loss of callus formation and rib bone r ...[more]

PMID: 30983567

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Project description:Skeletal muscle repair is driven by the coordinated self-renewal and fusion of myogenic stem and progenitor cells. Single-cell gene expression analyses of myogenesis have been hampered by the poor sampling of rare and transient cell states that are critical for muscle repair, and do not inform the spatial context that is important for myogenic differentiation. Here, we demonstrate how large-scale integration of single-cell and spatial transcriptomic data can overcome these limitations. We created a single-cell transcriptomic dataset of mouse skeletal muscle by integration, consensus annotation, and analysis of 23 newly collected scRNAseq datasets and 88 publicly available single-cell (scRNAseq) and single-nucleus (snRNAseq) RNA-sequencing datasets. The resulting dataset includes more than 365,000 cells and spans a wide range of ages, injury, and repair conditions. Together, these data enabled identification of the predominant cell types in skeletal muscle, and resolved cell subtypes, including endothelial subtypes distinguished by vessel-type of origin, fibro-adipogenic progenitors defined by functional roles, and many distinct immune populations. The representation of different experimental conditions and the depth of transcriptome coverage enabled robust profiling of sparsely expressed genes. We built a densely sampled transcriptomic model of myogenesis, from stem cell quiescence to myofiber maturation, and identified rare, transitional states of progenitor commitment and fusion that are poorly represented in individual datasets. We performed spatial RNA sequencing of mouse muscle at three time points after injury and used the integrated dataset as a reference to achieve a high-resolution, local deconvolution of cell subtypes. We also used the integrated dataset to explore ligand-receptor co-expression patterns and identify dynamic cell-cell interactions in muscle injury response. We provide a public web tool to enable interactive exploration and visualization of the data. Our work supports the utility of large-scale integration of single-cell transcriptomic data as a tool for biological discovery. David McKellar et al. integrate single-cell and -nuclear transcriptomic analyses of mouse skeletal muscle in homeostatic conditions or following injury. The resulting transcriptomic model of myogenesis identified rare, transitional states and cell subtypes that are poorly represented in individual datasets, providing a valuable resource for the field.

Dataset Information

Sox9+ messenger cells orchestrate large-scale skeletal regeneration in the mammalian rib.

Publications

Sox9+ messenger cells orchestrate large-scale skeletal regeneration in the mammalian rib.

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