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The Mohawk homeobox gene represents a marker and osteo-inhibitory factor in cranial suture stem cells [Mkx siRNA]

ABSTRACT: The regeneration of craniofacial bones of the mammalian skeleton necessitates the action of both intrinsic and extrinsic inductive factors from multiple cell types, which function in a hierarchical and temporal fashion to control the differentiation of osteogenic progenitors. Single-cell transcriptomics of developing mouse cranial suture recently identified a suture mesenchymal progenitor population with tendon- or ligament-associated gene expression profile previously uncharacterized. Here, we developed a Mohawk homeobox (MkxCG;R26RtdT) reporter mouse, finding that this teno-ligamentous gene identifies a cranial suture resident cell population within the adult mouse that gives rise to calvarial osteoblasts and osteocytes overtime during homeostatic conditions. Single cell RNA-Sequencing (scRNA-Seq) demonstrated that Mkx+ suture cells demonstrate a stem-like phenotype with expression of teno-ligamentous genes. Bone injury with Mkx+ cell ablation showed delayed bone healing. Remarkably, Mkx gene played a critical role as an osteo-inhibitory factor in cranial suture cells, as knockdown or knockout resulted in increased osteogenic differentiation. Furthermore, in vivo local deletion of Mkx in Mkx floxed mice resulted in robustly increased calvarial defect repair. Finally, we observed that mechanical stretch dynamically regulates Mkx expression in turn regulating calvarial cell osteogenesis. Overall, we identify Mkx+ cells within the suture mesenchyme as a progenitor cell population for adult craniofacial bones required for bone repair and Mkx itself as mechanical stretch responsive gene which functions to prevent osteogenic differentiation within the stem cell niche.

ORGANISM(S): Mus musculus

PROVIDER: GSE246238 | GEO | 2024/06/13

REPOSITORIES: GEO

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The Mohawk homeobox gene represents a marker and osteo-inhibitory factor in cranial suture stem cells

Project description:The regeneration of craniofacial bones of the mammalian skeleton necessitates the action of both intrinsic and extrinsic inductive factors from multiple cell types, which function in a hierarchical and temporal fashion to control the differentiation of osteogenic progenitors. Single-cell transcriptomics of developing mouse cranial suture recently identified a suture mesenchymal progenitor population with tendon- or ligament-associated gene expression profile previously uncharacterized. Here, we developed a Mohawk homeobox (MkxCG;R26RtdT) reporter mouse, finding that this teno-ligamentous gene identifies a cranial suture resident cell population within the adult mouse that gives rise to calvarial osteoblasts and osteocytes overtime during homeostatic conditions. Single cell RNA-Sequencing (scRNA-Seq) demonstrated that Mkx+ suture cells demonstrate a stem-like phenotype with expression of teno-ligamentous genes. Bone injury with Mkx+ cell ablation showed delayed bone healing. Remarkably, Mkx gene played a critical role as an osteo-inhibitory factor in cranial suture cells, as knockdown or knockout resulted in increased osteogenic differentiation. Furthermore, in vivo local deletion of Mkx in Mkx floxed mice resulted in robustly increased calvarial defect repair. Finally, we observed that mechanical stretch dynamically regulates Mkx expression in turn regulating calvarial cell osteogenesis. Overall, we identify Mkx+ cells within the suture mesenchyme as a progenitor cell population for adult craniofacial bones required for bone repair and Mkx itself as mechanical stretch responsive gene which functions to prevent osteogenic differentiation within the stem cell niche.

2024-06-13 | GSE245094 | GEO

Single-cell analysis identifies a key role for Hhip in murine coronal suture development

Project description:Craniofacial development depends on formation and maintenance of sutures between bones of the skull. In sutures, growth occurs at osteogenic fronts along the edge of each bone and suture mesenchyme separates adjacent bones. We performed single-cell RNA-seq analysis of the embryonic, murine coronal suture. Seven populations at E16.5 and nine at E18.5 comprised the suture mesenchyme, osteogenic cells, and associated populations. Expression of Hhip, an inhibitor of hedgehog (HH) signaling, marked a mesenchymal population distinct from other neurocranial sutures. At E18.5, Hhip-/- coronal osteogenic fronts were closely apposed and HH signaling was increased throughout the depleted suture mesenchyme compared to WT, demonstrating that Hhip is required for normal coronal suture development. Tracing of the neonatal Hhip-expressing population showed that descendant cells persisted in the coronal suture and contributed to calvarial bone growth. Our transcriptomic approach provides a rich resource for insight into normal and abnormal development.

2021-06-26 | GSE178899 | GEO

The developing mouse coronal suture at single-cell resolution

Project description:Sutures separate the flat bones of the skull and enable coordinated growth of the brain and overlying cranium. In order to uncover the cellular diversity within sutures, we conducted single-cell transcriptomic and histological analyses of the embryonic murine coronal suture. We identify Erg and Pthlh as early markers of osteogenic progenitors in sutures, and distinct pre-osteoblast signatures between the bone fronts and periosteum. diverse mesenchymal layers at the coronal suture, including multiple distinct meningeal layers below the suture, and ligamentous, ectocranial, and hypodermal layers above the sutureIn the ectocranial layers above the suture, we observe a ligament-like population spanning the frontal and parietal bones and expressing genes implicated in mechanosensation. Mesenchyme in and around the coronal suture is asymmetrically distributed between the frontal and parietal bones, and we identify different states of osteogenic cells extending from the bone fronts into the more mature bone, and a potential signature for sutural stem cellsIn the meningeal layers, we detect a potential chondrogenic periosteal dura population that may be involved in endochondral ossification that closes sutures. Expression of genes mutated in craniosynostosis is spread across diverse cell types, suggesting multiple points at which homeostasis can fail. This single-cell atlas provides a resource to understand the development of the coronal suture, the suture most commonly fused in craniosynostosis.

2021-06-17 | GSE163693 | GEO

BMP-dependent cellular dynamics during cranial suture establishment in zebrafish

Project description:Cranial sutures separate neighboring skull bones and contain skeletal stem cells that drive bone growth. A key question is how osteogenic activity is controlled to promote bone growth while preventing aberrant bone fusions during skull expansion. Here we integrate single-cell transcriptomics, in vivo expression validation, photoconversion-based lineage tracing, and a zebrafish craniosynostosis model to uncover key developmental transitions regulating bone formation during skull expansion. In addition to conservation of meninges and osteoblast lineage cells between zebrafish and mouse, single-cell transcriptomic analysis of the zebrafish skull reveals distinct subpopulations of suture mesenchyme that undergo transcriptomic changes during suture establishment. While lineage tracing with an osteoblast-specific nlsEOS reporter shows that bone formation largely occurs at suture edges, a subset of mesenchyme cells in the mid-suture region upregulate a suite of genes including BMP antagonists (e.g. grem1a) and pro-angiogenic factors. Further, lineage tracing with grem1a:nlsEOS reveals that this mid-suture subpopulation is largely non-osteogenic. In twist1b; tcf12 mutant zebrafish, a model for the coronal synostosis of Saethre-Chotzen Syndrome, reduction of grem1a+ mid-suture cells correlates with misregulated bone formation and reduced blood vessels at the coronal suture. In addition, combinatorial mutation of BMP antagonists enriched in the mid-suture subpopulation results in increased BMP signaling in the suture, misregulated bone formation, and abnormal suture morphology. These data support roles of a subset of mid-suture mesenchyme in locally promoting BMP antagonism that ensures proper suture morphology.

2024-07-11 | GSE223147 | GEO

A Single-Cell Transcriptomic Atlas Characterizes Age-Related Changes of Murine Cranial Stem Cell Niches

Project description:The bone tissue undergoes constant turnover, which relies on skeletal stem cells (SSCs) and/or mesenchymal stem cells (MSCs) and their niches. SSCs/MSCs and their perivascular niche within the bone marrow are well characterized in long bones. As for cranial bones, besides bone marrow, the suture mesenchyme has been identified as a unique niche for SSCs/MSCs of craniofacial bones. However, a comprehensive study of the two different cranial stem cell niches at single-cell resolution is still lacking. In addition, during the progression of aging, age-associated changes in cranial stem cell niches and resident cells remain uncovered. In this study, we investigated age-related changes in cranial stem cell niches via single-cell RNA sequencing (scRNA-seq).

2023-09-11 | GSE235176 | GEO

Transcriptional analysis of human cranial compartments with different embryonic origins

Project description:Previous investigations suggest that the different embryonic origins of the calvarial tissues (neural crest or mesoderm) may account for the different molecular mechanisms underlying sutural development. The aim of this study was to evaluate the differences in the gene expression of human cranial tissues and assess the presence of an expression signature reflecting their embryonic origins. Using microarray technology, we investigated global gene expression of cells from the frontal and parietal bones and the metopic and sagittal intrasutural mesenchyme (ISM) of four human fetal calvaria. Tissues samples were obtained from fetal crania of 4 normal human fetuses (two females ages 94 and 103 days and two males ages 97 and 98 days). All dural and extracranial soft tissues were removed from the parietal and frontal bones. 2-3 mm tissue compartments were excised from frontal and parietal bones and metopic and sagittal ISM. To avoid contamination with osteoblasts, ISM tissue was dissected from the central portion of each suture. Similarly, bone was harvested at least 3mm from the margin of the suture to avoid contamination with ISM. Media was changed every 3-4 days. After reaching 75-80% confluence, the cells were trypsinized with TrypLEExpress (Life Technologies, Denmark) and passaged. During the fourth and final passage, 180,000 cells were plated in triplicate in 6-well plates and cultured for 5 days followed by RNA extraction.

2015-08-03 | E-GEOD-62816 | biostudies-arrayexpress

Spatial transcriptomics reveals a role for sensory nerves in preserving cranial suture patency through modulation of BMP/TGFβ signaling

Project description:The patterning and ossification of the mammalian skeleton requires the coordinated actions of both intrinsic bone morphogens and extrinsic neurovascular signals, which function in a temporal and spatial fashion to control mesenchymal progenitor cell (MPC) fate. Here we show genetic inhibition of Tropomyosin receptor kinase A (TrkA) sensory nerve innervation of the developing cranium results in premature calvarial suture closure, associated with a decrease in suture MPC proliferation. In vitro, axons from peripheral afferent neurons derived from DRGs of wild type mice induce MPC proliferation in a spatially-restricted manner via a soluble factor when co-cultured in microfluidic chambers. Comparative spatial transcriptomic analysis of the cranial sutures in vivo confirmed a positive association between sensory axons and proliferative MPCs. SpatialTime analysis across the developing suture revealed regional-specific alterations in BMP and TGFβ signaling pathway transcripts in response to TrkA inhibition. RNA sequencing of DRG cell bodies following direct axonal co-culture with MPCs confirmed alterations in BMP/TGFβ signaling pathway transcripts. Among these, the BMP inhibitor FSTL1 (Follistatin-like 1) replicated key features of the neural-to-bone influence, including mitogenic and anti-osteogenic effects via inhibition of BMP/TGFβ signaling. Taken together, our results demonstrate that sensory nerve-derived signals, including FSTL1, function to coordinate cranial bone patterning by regulating MPC proliferation and differentiation in the suture mesenchyme.

2021-09-29 | GSE174313 | GEO

Skeletal Stem Cell Powering Cranial Suture Fate: An Answer to Craniosynostosis (bulk_RNA-seq)

Project description:Purpose: The cranial suture is a fibrous joint, and similar to the growth plates of the skeletal long bone, they serve as the major centers of calvarial vault morphogenesis. Our group’s identification of a skeletal stem cell isolated from the mouse tibial growth plate prompted us to investigate whether these skeletal stem cells are also resident in the mouse cranial sutures and if they govern postnatal suture patency or fusion. Results: We preformed a spatio-temporal profiling of the mouse cranial sutures by flow cytometry, demonstrating a significant decrease in the temporal representation of skeletal stem cells in fusing versus patent sutures. Moreover, canonical Wnt signaling has a significant impact on skeletal stem cells proliferation and thus representation within the suture, dictating fate: fusion or patency. Breeding an Axin2+/-LacZ mouse, with enhanced activation of canonical Wnt signaling to a Twist1+/− mouse, harboring a coronal craniosynostosis enriched the skeletal stem cell pool in coronal sutures, thereby preventing Twist1+/− craniosynostosis. Conclusions: Our findings suggest an imbalance and/or decrease in resident skeletal stem cells within the cranial sutures gives rise to craniosynostosis, however, restoring this representation by enriching skeletal stem cells within the suture can maintain patency.

2020-04-15 | GSE138880 | GEO

Skeletal Stem Cell Powering Cranial Suture Fate: An Answer to Craniosynostosis (scRNA-seq)

2020-04-15 | GSE138881 | GEO

Expression data from mouse calvarial suture mesenchymal cells

Project description:Axin2-expressing calvarial suture stem cells can contribute to calvarial development, homeostatic maintenance, repair, and regeneration. We used microarray to examine the gene expression profiles of Axin2-expressing suture stem cells and Axin2-negative cells in suture mesenchyme.

2015-11-11 | GSE74849 | GEO

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