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Spatial transcriptomic analysis of a pre-clinical NF1 pseudarthrosis fracture model

ABSTRACT: Spatial transcriptomic analysis of a pre-clinical NF1 pseudarthrosis fracture model

PROVIDER: PRJNA901981 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22302417_1.fastq.gz	Fastqsanger.gz
	SRR22302417_2.fastq.gz	Fastqsanger.gz
	SRR22302418_1.fastq.gz	Fastqsanger.gz
	SRR22302418_2.fastq.gz	Fastqsanger.gz

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Spatial transcriptomic analysis of a pre-clinical NF1 pseudarthrosis fracture model

Project description:Patients with Neurofibromatosis Type 1 (NF1) present with fracture pseudarthroses, though the exact mechanism underlying this abnormal healing remains unknown. Here, we performed spatial transcriptomics to spatially-define the molecular signatures across endochondral healing following fracture. Integrating single-cell sequencing of patient fracture-derived primary cells, our results provide a dynamic cellular context to the molecular dysregulation associated with somatic fracture healing defects in NF1.

2024-07-12 | GSE218046 | GEO

Molecular dissection of somatic NF1 pseudarthrosis

Project description:Neurofibromatosis Type 1 (NF1) is a tumor predisposition syndrome with pleiotropic somatic manifestations, including formation of bone pseudarthrosis after fracture. The pathogenesis of NF1 pseudarthroses remains unclear, though defects in osteogenesis have been posited. Here, we applied time-series single-cell RNA-sequencing (scRNAseq) to patient-matched control and pseudarthrosis-derived primary bone mesenchymal stromal cells (MSCs). We show that osteogenesis occurs in NF1-/- MSCs. In contrast, expression of genetic pathways associated with skeletal mineralization were reduced in NF1-/- cells compared to co-cultured NF1+/- fracture-derived cells.

2022-12-13 | GSE196652 | GEO

Effect of MEKi on NF1 pseudarthrosis primary cells

Project description:Background: Neurofibromatosis type 1 (NF1) is a genetic condition predisposing children to fracture pseudarthroses. MEK inhibitors are FDA-approved or under study for the treatment of malignant pathologies associated with NF1, though their potential to treat pseudarthrosis is largely unknown. Methods: Primary cells cultured from control bone (i.e., iliac crest) or fracture pseudarthroses from children with NF1 were treated with vehicle or the MEK inhibitors trametinib or selumetinib. Gene expression was evaluated by transcriptome sequencing (RNAseq), and activation of the downstream signaling pathway was evaluated by western blotting. Results were replicated in an independent cohort of patient pseudarthrosis-derived primary cells. Results: We confirmed increased MAPK signaling in pseudarthrosis samples compared to patient-matched control samples. Pseudarthrosis samples were reproducibly associated with reduced expression of gene signatures implicated in osteoblast differentiation, skeletal development, and formation of the extracellular matrix. Expression of these gene signatures was significantly rescued following treatment with selumetinib, and to a lesser extent trametinib, concomitant with reduced MAPK signaling activation. Conclusions: Our study utilized patient-derived primary cells to demonstrate the molecular signatures associated with fracture pseudarthrosis and how this molecular dysregulation was reversed with MEK inhibitor treatment. Clinical relevance: MEK inhibitors may be repurposed to promote healing of fracture pseudarthroses in children with NF1.

2025-05-29 | GSE277653 | GEO

Single nuclei RNAseq of the bone fracture callus of Prss56-Nf1 KO mice

Project description:Periosteum deficiency affects bone regeneration, especially in the case of the bone disorder congenital pseudarthrosis of the tibia (CPT). We investigated a new mouse model of CPT caused by Nf1 inactivation in boundary cap-derivatives, the Prss56Cre; R26tdTom; Nf1fl/fl model. To investigate altered healing in this CPT model, we generated a dataset of the injured periosteum and fracture callus at day-7 post fracture from Prss56Cre; R26tdTom; Nf1fl/fl mice.

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Single nuclei RNAseq of the human periosteum from patients with congenital pseudarthrosis of the tibia

Project description:Congenital pseudarthrosis of the tibia (CPT) is a severe pediatric disorder affecting children. CPT is characterized by tibial bowing at birth leading to spontaneous fracture and fibrous non-union. Our study showed the presence of biallelic inactivation of the NF1 gene in the periosteum at the pseudarthrosis site. To understand the impact of NF1 mutation on the periosteum, we performed single nuclei RNAseq of pathological periosteum collected from the pseudarthrosis site and of non-pathological periosteum collected from the iliac crest of 3 CPT patients.

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Molecular dissection of somatic NF1 pseudarthrosis

Project description:Molecular dissection of somatic NF1 pseudarthrosis

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RNAseq of periosteal stem/progenitor cells from patients with congenital pseudarthrosis of the tibia

2024-07-24 | GSE234071 | GEO

Effect of MEKi on NF1 pseudarthrosis primary cells

Project description:Effect of MEKi on NF1 pseudarthrosis primary cells

| PRJNA1163293 | ENA

Single-cell RNAseq analysis of Nf1-deficient Prss56-derived cells from spinal columns of young and old mice

Project description:Neurofibromatosis type 1 (NF1) is a genetic disorder affecting 1 in 3000 people due to heterozygous mutations in the NF1 gene. Patients with NF1 can develop multiple symptoms, such as neurofibromas, skin hyperpigmentation, and bone abnormalities, including tibial pseudarthrosis and spine deformity. Here, we aimed to elucidate the cellular origin and pathogenic mechanism of NF1 spine deformity. Prss56-Nf1 knockout (KO) mouse is a model that recapitulates neurofibromas and pseudarthrosis by carrying Nf1 gene inactivation in Prss56-expressing boundary cap (BC) cells, a neural crest subset, and their derivatives. Through transcriptomics analysis, we explored the molecular changes that occur through time in Prss56-derived cells populating the vertebral column of Prss56-Nf1 KO mice.

2025-12-30 | GSE305286 | GEO

Spatial transcriptomics implicates impaired BMP signaling in NF1 fracture pseudarthrosis in murine and patient tissues.

Project description:The neurofibromatosis type 1 (NF1) RASopathy is associated with persistent fibrotic nonunions (pseudarthrosis) in human and mouse skeletal tissue. Here, we performed spatial transcriptomics to define the molecular signatures occurring during normal endochondral healing following fracture in mice. Within the control fracture callus, we observed spatially restricted activation of morphogenetic pathways, such as TGF-β, WNT, and BMP. To investigate the molecular mechanisms contributing to Nf1-deficient delayed fracture healing, we performed spatial transcriptomic analysis on a Postn-cre;Nf1fl/- (Nf1Postn) fracture callus. Transcriptional analyses, subsequently confirmed through phospho-SMAD1/5/8 immunohistochemistry, demonstrated a lack of BMP pathway induction in Nf1Postn mice. To gain further insight into the human condition, we performed spatial transcriptomic analysis of fracture pseudarthrosis tissue from a patient with NF1. Analyses detected increased MAPK signaling at the fibrocartilaginous-osseus junction. Similar to that in the Nf1Postn fracture, BMP pathway activation was absent within the pseudarthrosis tissue. Our results demonstrate the feasibility of delineating the molecular and tissue-specific heterogeneity inherent in complex regenerative processes, such as fracture healing, and reconstructing phase transitions representing endochondral bone formation in vivo. Furthermore, our results provide in situ molecular evidence of impaired BMP signaling underlying NF1 pseudarthrosis, potentially informing the clinical relevance of off-label BMP2 as a therapeutic intervention.

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