Spatial transcriptomics reveals a role for sensory nerves in preserving cranial suture patency through modulation of BMP/TGFβ signaling
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ABSTRACT:
PROVIDER: PRJNA729419 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14508748_1.fastq.gz | Fastqsanger.gz | |||
| SRR14508748_2.fastq.gz | Fastqsanger.gz | |||
| SRR14508749_1.fastq.gz | Fastqsanger.gz | |||
| SRR14508749_2.fastq.gz | Fastqsanger.gz | |||
| SRR14508750_1.fastq.gz | Fastqsanger.gz |
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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
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 | GSE138881 | GEO
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
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
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
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 | GSE246238 | GEO
Project description:Assaying gene expression in sutural bone fragments from patients diagnosed with non-syndromic craniosynostosis. Sutural fragments were collected from both the fused and patent cranial suture of infants during cranial vault reconstruction. Gene expression was compared between the patent and fused sutures using the paired t-test. The aim was to identify thoses genes significantly differentially expressed in fused suture relative to patent. Total RNA isolated from patent and fused human cranial sutures was assayed. Expression in synostosed suture was compared to patent suture.
2013-09-12 | E-GEOD-50796 | biostudies-arrayexpress
Project description:BMP-dependent cellular dynamics during cranial suture establishment in zebrafish
| PRJNA925134 | ENA
Project description:Skeletal Stem Cell Powering Cranial Suture Fate: An Answer to Craniosynostosis
| PRJNA577679 | ENA
Project description:Assaying gene expression in sutural bone fragments from patients diagnosed with non-syndromic craniosynostosis. Sutural fragments were collected from both the fused and patent cranial suture of infants during cranial vault reconstruction. Gene expression was compared between the patent and fused sutures using the paired t-test. The aim was to identify thoses genes significantly differentially expressed in fused suture relative to patent.
2013-09-12 | GSE50796 | GEO