A multi-stem cell basis for craniosynostosis and calvarial mineralization
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA973103 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24601203_1.fastq.gz | Fastqsanger.gz | |||
| SRR24601203_2.fastq.gz | Fastqsanger.gz | |||
| SRR24601204_1.fastq.gz | Fastqsanger.gz | |||
| SRR24601204_2.fastq.gz | Fastqsanger.gz | |||
| SRR24601205_1.fastq.gz | Fastqsanger.gz |
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Project description:FACS-sorted 2 bulk cell populations from mouse calvarial sutures (P7) were subjected to RNA sequencing. The samples were CTSK+ calvarial stem cells (labeled as PSC here) and DDR2+ calvarial stem cells isolated from CTSK-Cre;mTmG mice (n=5). The aim of this study was to obtain differentially expressed gene list for two different cell types as well as compare transcriptional profile between these populations.
2023-05-21 | GSE232652 | GEO
Project description:Craniosynostosis is a group of disorders of premature calvarial suture fusion. The identity of the calvarial stem cells (CSCs) that produce fusion-driving osteoblasts in craniosynostosis remains poorly understood. Here we show that both physiologic calvarial mineralization and pathologic calvarial fusion in craniosynostosis reflect the interaction of two separate stem cell lineages; a previously identified cathepsin K (CTSK) lineage CSC1 (CTSK+ CSC) and a separate discoidin domain-containing receptor 2 (DDR2) lineage stem cell (DDR2+ CSC) that we identified in this study. Deletion of Twist1, a gene associated with craniosynostosis in humans2,3, solely in CTSK+ CSCs is sufficient to drive craniosynostosis in mice, but the sites that are destined to fuse exhibit an unexpected depletion of CTSK+ CSCs and a corresponding expansion of DDR2+ CSCs, with DDR2+ CSC expansion being a direct maladaptive response to CTSK+ CSC depletion. DDR2+ CSCs display full stemness features, and our results establish the presence of two distinct stem cell lineages in the sutures, with both populations contributing to physiologic calvarial mineralization. DDR2+ CSCs mediate a distinct form of endochondral ossification without the typical haematopoietic marrow formation. Implantation of DDR2+ CSCs into suture sites is sufficient to induce fusion, and this phenotype was prevented by co-transplantation of CTSK+ CSCs. Finally, the human counterparts of DDR2+ CSCs and CTSK+ CSCs display conserved functional properties in xenograft assays. The interaction between these two stem cell populations provides a new biologic interface for the modulation of calvarial mineralization and suture patency.
| S-EPMC10799660 | biostudies-literature
Project description:Craniosynostosis (CS) is the congenital premature fusion of one or more cranial sutures and represents the more prevalent craniofacial malformation in humans, with an overall incidence of 1 out of 2000-3000 live births. Non-syndromic craniosynostoses (NSC) are believed to be multifactorial disorders, with a strong genetic component, due to possible gene–gene or gene–environment interactions that remain to be clearly identified. In this study we delved into the molecular signaling acting in calvarial tissue and cells from patients affected by nonsynodromic midline craniosynostosis, using a comparative analysis between fused and unfused sutures of each affected individuals. Using comparative microarray tissue gene expression profiling we have identified a subset of genes involved in the structure and function of the primary cilium, including the Bardet-Biedl syndrome 9 (BBS9) gene, which was recently associated to sagittal synostosis in a GWAS study. We therefore characterized BBS9 expression and cilium-related signaling in cells isolated from patients’ calvarial bone.
2018-05-31 | GSE79386 | GEO
Project description:Craniosynostosis is a disease defined by premature fusion of one or more cranial sutures. The mechanistic pathology of isolated single-suture craniosynostosis is complex and while a number of genetic biomarkers and environmental predispositions have been identified, in many cases the causes remain controversial and inconclusive at best. After controlling for variables contributing to potential bias, FGF7, SFRP4, and VCAM1 emerged as potential genetic biomarkers for single-suture craniosynostosis due to their significantly large changes in gene expression compared to the control population. Furthermore, pathway analysis implicated focal adhesion and extracellular matrix (ECM)-receptor interaction as differentially regulated gene networks when comparing all cases of single-suture synostosis and controls. Lastly, overall gene expression was found to be highly conserved between coronal and metopic cases, as evidenced by the fact that WNT2 and IGFBP2 were the only differentially regulated genes identified in a direct comparison. These results not only confirm the roles of previously reported craniosynostosis-related targets but also introduce novel genetic biomarkers and pathways that may play critical roles in its pathogenesis.
2012-03-04 | GSE27976 | GEO
Project description:Mutations within FGFR2 are causative for various craniosynostosis syndromes. The mandibular dysmorphogenesis in these syndromes has rarely been quantitatively characterized prenatally and the cellular and molecular mechanism involved is unclear. To investigate the effects of FGFR2 mutations on development of the mandible, micro-computed tomography (μCT) images were acquired using newborn mice of three Fgfr2-mutant lines associated with Apert and Crouzon craniosynostosis syndromes. Euclidean Distance Matrix Analysis and analysis of relative bone mineral density (BMD) of 3D μCT images revealed differences in mandible morphology and BMD between the mice carrying the Fgfr2 mutations and their unaffected littermates. We further investigated the mechanism for mandibular dysgenesis in the Fgfr2+/S252W (Fgfr2S252W) mouse model that showed the most severe phenotypes. At E16.5, Fgfr2S252W embryos showed an increase in the size of the osteogenic anlagen and Meckel’s cartilage (MC) and altered microarchitecture and mineralization in the mandible relative to unaffected littermates. Laser capture microdissection and RNA-Seq analysis revealed transcriptomic changes in the mandibular bone, highlighting increased expression of genes undergoing osteoclast differentiation and dysregulated genes active in bone mineralization. Increased osteoclastic activity in the mandible of Fgfr2S252W embryos was confirmed and elevated inorganic pyrophosphate concentration was identified due to upregulated expression of Enpp1 and Ank. In contrast, increased proliferation in MC was observed at E12.5. These findings provide evidence that gain-of-function mutations in FGFRs differentially affect intramembranous ossification of dermal bone and cartilage formation contributing to mandibular dysmorphogenesis in craniosynostosis syndromes.
2018-11-07 | GSE121780 | 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:Craniosynostosis is a disease defined by premature fusion of one or more cranial sutures. The mechanistic pathology of isolated single-suture craniosynostosis is complex and while a number of genetic biomarkers and environmental predispositions have been identified, in many cases the causes remain controversial and inconclusive at best. After controlling for variables contributing to potential bias, FGF7, SFRP4, and VCAM1 emerged as potential genetic biomarkers for single-suture craniosynostosis due to their significantly large changes in gene expression compared to the control population. Furthermore, pathway analysis implicated focal adhesion and extracellular matrix (ECM)-receptor interaction as differentially regulated gene networks when comparing all cases of single-suture synostosis and controls. Lastly, overall gene expression was found to be highly conserved between coronal and metopic cases, as evidenced by the fact that WNT2 and IGFBP2 were the only differentially regulated genes identified in a direct comparison. These results not only confirm the roles of previously reported craniosynostosis-related targets but also introduce novel genetic biomarkers and pathways that may play critical roles in its pathogenesis. In this study, gene expression data from 199 patients with isolated sagittal (n= 100), unilateral coronal (n = 50), and metopic (n = 49) synostosis are compared against both a control population (n = 50), as well as each other.
2012-03-04 | E-GEOD-27976 | biostudies-arrayexpress
Project description:Suture mesenchymal stem cell (MSC) drives calvarial suture development, homeostasis, and regeneration. Its loss leads to craniosynostosis, a prevailing craniofacial disorder characterized by premature suture closure. Ribosome biogenesis, historically thought to be a static house-keeping process, is now known to have tissue-specific roles. However, the functional specificity of ribosome biogenesis in suture MSCs remains largely unexplored, hampering development of therapeutic strategies for craniofacial tissue regeneration. We genetically perturb ribosome biogenesis using Snord118, a small nucleolar RNA (snoRNA) required for ribosomal RNA (rRNA) maturation. MSC specific conditional knockout (cKO) of Snord118 in mice leads to p53 activation, cell death, mesenchymal and MSC loss, impaired osteogenic and osteoclastic activity, resulting in suture growth and craniosynostosis defects. Using our newly established human induced pluripotent stem cell (iPSC)-derived MSCs combined with ribosome profiling, we found that SNORD118deficiency in MSCs causes global translation dysregulations and downregulation of complement pathway, a part of innate immune system with selective but poorly characterized physiological functions in craniofacial tissue homeostasis. Overall, ribosome biogenesis controls suture MSC fate via selective regulation of complement pathway.
2023-12-20 | GSE223615 | GEO
Project description:Suture mesenchymal stem cell (MSC) drives calvarial suture development, homeostasis, and regeneration. Its loss leads to craniosynostosis, a prevailing craniofacial disorder characterized by premature suture closure. Ribosome biogenesis, historically thought to be a static house-keeping process, is now known to have tissue-specific roles. However, the functional specificity of ribosome biogenesis in suture MSCs remains largely unexplored, hampering development of therapeutic strategies for craniofacial tissue regeneration. We genetically perturb ribosome biogenesis using Snord118, a small nucleolar RNA (snoRNA) required for ribosomal RNA (rRNA) maturation. MSC specific conditional knockout (cKO) of Snord118 in mice leads to p53 activation, cell death, mesenchymal and MSC loss, impaired osteogenic and osteoclastic activity, resulting in suture growth and craniosynostosis defects. Using our newly established human induced pluripotent stem cell (iPSC)-derived MSCs combined with ribosome profiling, we found that SNORD118deficiency in MSCs causes global translation dysregulations and downregulation of complement pathway, a part of innate immune system with selective but poorly characterized physiological functions in craniofacial tissue homeostasis. Overall, ribosome biogenesis controls suture MSC fate via selective regulation of complement pathway.
2023-12-20 | GSE223614 | GEO