Muscle denervation promotes functional interactions between glial and mesenchymal cells through NGFR and NGF
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA915640 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22890500_1.fastq.gz | Fastqsanger.gz | |||
| SRR22890500_2.fastq.gz | Fastqsanger.gz | |||
| SRR22890501_1.fastq.gz | Fastqsanger.gz | |||
| SRR22890501_2.fastq.gz | Fastqsanger.gz | |||
| SRR22890502_1.fastq.gz | Fastqsanger.gz |
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Project description:We have performed parallel scRNA-seq and snATAC-seq analysis of skeletal muscles subjected to sciatic nerve transection to delineate cell type-specific patterns of gene expression and chromatin accessibility at different time-points post-denervation. This analysis revealed that, unlike muscle injury, denervation leads to the selective activation of specific muscle-resident cell types, such as glial cells and a population of mesenchymal cells marked by the expression of Thy1/CD90.
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Project description:We performed scRNA-seq/snATAC-seq of skeletal muscles post sciatic nerve transection to delineate cell type-specific patterns of gene expression/chromatin accessibility at different time points post-denervation. Unlike myotrauma, denervation selectively activates glial cells and Thy1/CD90-expressing mesenchymal cells. Glial cells expressed Ngf receptor (Ngfr) and were located near neuromuscular junctions (NMJs), close to Thy1/CD90-expressing cells, which provided the main cellular source of NGF post-denervation. Functional communication between these cells was mediated by NGF/NGFR, as either recombinant NGF or co-culture with Thy1/CD90-expressing cells could increase glial cell number ex vivo. Pseudo-time analysis in glial cells revealed an initial bifurcation into processes related to either cellular de-differentiation/commitment to specialized cell types (e.g., Schwann cells), or failure to promote nerve regeneration, leading to extracellular matrix remodeling toward fibrosis. Thus, interactions between denervation-activated Thy1/CD90-expressing and glial cells represent an early abortive process toward NMJs repair, ensued by the conversion of denervated muscles into an environment hostile for NMJ repair.
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Project description:The cranial sutures are fibrous joints containing skeletal progenitor cells, which maintain homeostasis of the uninjured skull or participate in healing the skull after injury. Nerve growth factor (NGF) via its high-affinity receptor tropomyosin receptor kinase A (TrkA) regulates skeletal re-innervation, which is essential for later elements of bone repair, including revascularization and bone matrix deposition. However, emerging evidence suggests that NGF signaling may have more pleiotropic effects in bone repair than previously considered. In addition to induction of nerve ingrowth and promotion of nerve survival, pro-NGF may bind to its low-affinity receptor Ngfr (p75, Cd271), which is present in a variety of mesenchymal cells. p75 expression has been correlated to cell migration and invasion in multiple cell types. NGF binding to the p75 receptor stimulates migration and initiates recruitment of various adaptors, which activate NF-κB, RhoA, and c-Jun N-terminal kinase (JNK) signaling. In this study, single cell transcriptomics highlights altered signaling pathway activation and impaired cellular migration with p75 conditional gene deletion in PDGFRα-expressing cells.
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Project description:It has been proposed that bone marrow contributes to the pathogenesis of arteriosclerosis. Nerve growth factor receptor (NGFR) is expressed in bone marrow stromal cells; it is also present in peripheral blood and ischemic coronary arteries. We hypothesized that bone marrow-derived NGFR-positive (NGFR+) cells regulate arterial remodeling. We found that human NGFR+ mononuclear cells (MNCs) in peripheral blood expressed markers for plasmacytoid dendritic cells (DCs) and were susceptible to apoptosis in response to proNGF secreted by activated arterial smooth muscle cells (SMCs). Bone marrow-specific depletion of NGFR+ cells increased neointimal formation following arterial ligation in mice. Bone marrow-derived NGFR+ cells accumulated in the neointima and underwent apoptosis. In contrast, in a bone marrow-specific NGFR-knockout model, SMCs occupied the neointima with augmented proliferation. NGFR+ cells in the neointima promoted mannose receptor C-type 1-positive antiinflammatory macrophage accumulation and secreted antiinflammatory IL-10, thereby inhibiting SMC proliferation in the neointima. In patients with acute coronary syndrome (ACS), NGFR+ peripheral MNCs increased after ACS onset. Multiple linear regression analysis showed that an insufficient increase in NGFR+ peripheral MNCs in ACS was an adjusted independent risk factor for 9-month intimal progression of a nontargeted lesion. Taken together, these observations imply that bone marrow-derived NGFR+ DCs are suppressors of arteriosclerosis.
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Project description:The expression of the Nerve growth factor receptor (NGFR) was described in follicular dendritic cells (FDCs), the major lymphoid stromal cell (LSC) compartment regulating B-cell activation within germinal centers (GCs). However, the role of NGFR in humoral response is not well defined. In this work, we have studied the effect of Ngfr KO in LNs organization and function. Ngfr KO led to spontaneous GC formation and expansion of GC B-cell compartment that were related on Ngfr depletion in non-hematopoietic radioresistant compartment. In agreement, Ngfr KO mice showed alterations in LSC with an increased frequency of FDCs harboring an activated phenotype characterized by the overexpression of CD21/35, MAdCAM-1, and VCAM-1. Moreover, Ngfr KO mice showed GC ectopic location, loss of polarization, impaired high-affinity antibody production, and increased circulating autoantibodies. In addition, Ngfr KO/Bcl2 Tg mice displayed increased levels of autoantibodies, higher incidence of autoimmunity, and decreased overall survival. Our work shows that NGFR maintains GC structure and functionality being involved in the regulation of antibody production and immune tolerance.
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Project description:This study investigated the role of sympathetic denervation in enhancing CAR T cell anti-tumor efficacy in renal clear cell carcinoma. By blocking the NGF pathway with antibodies, we demonstrated reduced sympathetic nerve distribution and delayed tumor progression. Furthermore, CAR T cells engineered to secrete NGF scFv achieved tumor immunosympathectomy, leading to improved anti-tumor effects. RNA sequencing revealed that this enhancement was linked to reduced terminal exhaustion in CD8 T cells and inhibited macrophage polarization from M1 to M2, promoting a robust anti-tumor immune state. Additionally, splenic T cells exhibited a stronger immune effector phenotype following the infusion of NGF scFv-secreting CAR T cells. These findings suggest that immunosympathectomy may represent a novel strategy to mitigate tumor-induced immunosuppression and improve CAR T cell efficacy in solid tumors.
2024-12-18 | GSE279394 | GEO
Project description:This study investigated the role of sympathetic denervation in enhancing CAR T cell anti-tumor efficacy in renal clear cell carcinoma. By blocking the NGF pathway with antibodies, we demonstrated reduced sympathetic nerve distribution and delayed tumor progression. Furthermore, CAR T cells engineered to secrete NGF scFv achieved tumor immunosympathectomy, leading to improved anti-tumor effects. RNA sequencing revealed that this enhancement was linked to reduced terminal exhaustion in CD8 T cells and inhibited macrophage polarization from M1 to M2, promoting a robust anti-tumor immune state. Additionally, splenic T cells exhibited a stronger immune effector phenotype following the infusion of NGF scFv-secreting CAR T cells. These findings suggest that immunosympathectomy may represent a novel strategy to mitigate tumor-induced immunosuppression and improve CAR T cell efficacy in solid tumors.
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Project description:Gene expression and H3K27ac changes upon Rat gastrognemius muscle denervation
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Project description:Expression profiling of PC12 cells stably transfected with GFP, GFP-SH2-Bb, or GFP-SH2-Bb(R555E), treated with or without NGF for 6h Keywords: response to NGF
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Project description:Secreted extracellular vesicles are known to influence the tumor microenvironment and promote metastasis. In this work, we have analyzed the involvement of extracellular vesicles in the establishment of lymph node pre-metastatic niches by melanoma cells. We found that small extracellular vesicles (sEVs) derived from highly metastatic melanoma cell lines spread broadly through the lymphatic system and were taken up by lymphatic endothelial cells, reinforcing lymph node metastasis. Melanoma-derived sEVs induce lymphangiogenesis, a hallmark of pre-metastatic niche formation, in vitro and in lymphoreporter mice in vivo. We found that neural growth factor receptor (NGFR) is secreted in melanoma-derived small extracellular vesicles and shuttled to lymphatic endothelial cells, inducing lymphangiogenesis and tumor cell adhesion through the activation of ERK and NF-B pathways and ICAM1 expression. Importantly, ablation or inhibition of NGFR in sEVs reversed the lymphangiogenic phenotype, decreased melanoma lymph node metastasis and extended the survival. Importantly, analysis of NGFR expression in lymph node metastases and matched primary tumors shows that levels of MITF+NGFR+ lymph node metastatic cells are correlated with disease outcome. Our data support the idea that NGFR secreted in sEVs favors lymph node pre-metastatic niche formation and lymph node metastasis in melanoma
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