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Effect of MEKi on NF1 pseudarthrosis primary cells

ABSTRACT: Effect of MEKi on NF1 pseudarthrosis primary cells

PROVIDER: PRJNA1163293 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30734731_1.fastq.gz	Fastqsanger.gz
	SRR30734731_2.fastq.gz	Fastqsanger.gz
	SRR30734732_1.fastq.gz	Fastqsanger.gz
	SRR30734732_2.fastq.gz	Fastqsanger.gz
	SRR30734733_1.fastq.gz	Fastqsanger.gz

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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

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.

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Molecular dissection of somatic NF1 pseudarthrosis

Project description:Molecular dissection of somatic NF1 pseudarthrosis

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

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

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

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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.

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Project description:One of the major primary features of the neurocutaneous genetic disorder Neurofibromatosis type 1 are the hyperpigmentary café-au-lait macules where dysregulation of melanocyte development, proliferation and differentiation is considered to play a key etiopathogenic role. To gain better insight in the possible role of the tumor suppressor gene NF1, a transcriptomic microarray analysis was performed on human NF1 heterozygous (NF1+/-) melanocytes of a Neurofibromatosis type 1 patient and NF1 wild type (NF1+/+) melanocytes of a healthy control patient, both cultured from normally pigmented and hyperpigmented lesional café-au-lait skin. Out of 13,850 unique genes, a total of 137 had a significant twofold or more up- (72) or down-regulated (65) expression in NF1+/- melanocytes compared to NF1+/+ melanocytes (genotype effect). Considering possible intrinsic genetic variation in lesional skin, melanocytes showed a total of 51 genes having a significant twofold or more up- (37) or down-regulated (14) expression when they were cultured from hyperpigmentary café-au-lait skin compared to normally pigmented skin (lesional skin type effect). NF1+/- café-au-lait skin melanocytes showed 468 genes with a significant two-fold or more up- (183) or down-regulated (285) expression going beyond the sum of the separate main effects (interaction). Detailed analysis enabled the identification of several modulated genes in NF1+/- (café-au-lait skin) melanocytes, mainly involved in controlling cell proliferation and cell maintenance, in cell adhesion and, surprisingly, in the immune response. An interesting finding was that a high number of transcription factor genes were differentially modulated, among which a specific subset - important in melanocyte-lineage development - showed downregulation in a transcriptional cis-regulatory network governing the activation of the melanocyte-specific dopachrome tautomerase (DCT) gene.

2005-02-05 | E-MEXP-258 | biostudies-arrayexpress

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.

2024-07-24 | GSE232517 | GEO

Genome-wide gene expression analysis of neurofibroma-derived NF1+/- and NF1-/- Schwann cells

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