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A BDNF-TrkB autocrine loop enhances senescent cell viability [RNA-seq]

ABSTRACT: Cellular senescence is characterized by cell cycle arrest, resistance to apoptosis, and a senescence-associated secretory phenotype (SASP) whereby cells secrete pro-inflammatory and tissue-remodeling factors. Given that the SASP exacerbates age-associated pathologies, some aging interventions selectively eliminate senescent cells. In this study, a drug library screen uncovered TrkB (NTRK2) inhibitors as selectively capable of triggering apoptosis of senescent, but not proliferating, human fibroblasts. Senescent cells expressed high levels of TrkB, which supported senescent cell viability, and secreted the TrkB ligand BDNF. The reduced viability of senescent cells after ablating BDNF function supported an autocrine function for TrkB and BDNF, and the increased expression of BCL2L2 through ERK5, downstream of BDNF-TrkB, favored senescent cell survival. Strikingly, treatment with TrkB inhibitors reduced the accumulation of senescent cells in aged mouse organs. Our results suggest that the SASP factor BDNF promotes cell survival by activating TrkB and is a promising therapeutic target to reduce the senescent cell burden.

ORGANISM(S): Homo sapiens

PROVIDER: GSE190998 | GEO | 2022/09/20

REPOSITORIES: GEO

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The YAP-TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress [scRNA-seq]

Project description:Sublethal cell damage can trigger a complex adaptive program known as senescence, characterized by growth arrest, resistance to apoptosis, and a senescence-associated secretory phenotype (SASP). As senescent cells accumulating in aging organs are linked to many age-associated diseases, senotherapeutic strategies are actively sought to eliminate them. Here, a whole-genome CRISPR knockout screen revealed that proteins in the YAP-TEAD pathway influenced senescent cell viability. Accordingly, treating senescent cells with a drug that inhibited this pathway, Verteporfin (VPF), selectively triggered apoptotic cell death and derepressed DDIT4, in turn inhibiting mTOR. Reducing mTOR function in senescent cells diminished endoplasmic reticulum (ER) biogenesis, causing ER stress and apoptosis due to high demands on ER function by the SASP. Importantly, VPF treatment decreased senescent cell numbers in the organs of old mice and mice exhibiting doxorubicin-induced senescence. We present a novel senolytic strategy that eliminates senescent cells by hindering ER activity required for SASP production.

2023-07-13 | GSE221117 | GEO

The YAP-TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress [bulk RNA-seq]

2023-07-13 | GSE221104 | GEO

The YAP-TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress [scRNA-seq_mouse]

2023-07-13 | GSE232273 | GEO

Stat3-Bdnf-TrkB axis promotes alveolar regeneration [scRNA-seq]

Project description:Regenerating new alveolar epithelium is essential for recovery from many lung diseases. This multi-cellular regenerative process occurs when type II alveolar pneumocytes (AT2), with support from mesenchymal niche cells, proliferate to generate more AT2 cells and transdifferentiate in type I pneumocytes. To elucidate how coordinated events between AT2 cells and mesenchyme restore alveolar epithelium we used unbiased genome-wide analysis of chromatin accessibility and gene expression in both cell types following acute lung injury. We observed that chromatin acessability in AT2 cells changes signficantly following acute lung injury. Newly accessible chromatin reveals new STAT3 binding motifs adjacent to genes that regulate essential regenerative pathways in AT2 cells. Restoration of alveolar structures following both sterile and infectious lung injuries was inhibited when STAT3 signaling was lost in AT2 cells. Single-cell transcriptome analysis of regenerating AT2 cells identified brain neurotrophic factor (Bdnf) as the sole STAT3 target gene whose chromatin becomes newly accessible in a regenerating population of AT2 cells. BDNF increased alveolar organoid size and forming efficiency in murine and human models. The receptor for BDNF, TrkB, is uniquely? expressed on mesenchymal alveolar niche cells (MANC). Exposure of BDNF to TrkB increases expression of fibroblast growth factor 7 (Fgf7), an essential regenerative cytokine, in MANCs. Blocking Bdnf signaling with a TrkB receptor antagonist abrogated murine and human alveolar organoid formation. Finally, a small molecule TrkB agonist improved functional and histological outcomes in vivo following sterile and infectious lung injuries. Collectively, these data highlight the biological and therapeutic importance of the Stat3-Bdnf-TrkB axis in orchestrating alveolar epithelial regeneration

2020-06-01 | GSE132533 | GEO

Stat3-Bdnf-TrkB axis promotes alveolar regeneration [ATAC-seq]

2020-06-01 | GSE132534 | GEO

Twist, Snail and Zeb1 targets in the context of TrkB

Project description:RK3E cells expressing TrkB and BDNF: comparison control (sh-EGFP) and sh-Twist, sh-Snail or sh-Zeb1

2011-10-12 | E-MTAB-456 | biostudies-arrayexpress

RNA-seq of human neurons derived from mutant embryonic stem cell line lacking the BDNF receptor TrkB treated with the natural TrkC receptor agonist Neurotrophin-3

Project description:RNAseq data indicate that in the human brain, most neurons co-express the brain-derived neurotrophic factor (BDNF) receptor TrkB and the Neurotrophin-3 (NT3) receptor TrkC. Because NT3 can also activate TrkB and TrkB is expressed at higher levels compared with TrkC, it has been difficult thus far to explore TrkC-mediated signaling. To this end, neurons were generated from human embryonic stem cells lacking the BDNF receptor TrkB using CRISPR/Cas9. These neurons were found to respond to very low concentrations of NT3, lower than the concentrations of BDNF needed to activate TrkB. In order to compare the transcriptional changes following treatment with NT3 RNA-seq analysis was performed and the results compared with those previously obtained following treatment of wild-type neurons with BDNF Merkouris et al. PMID: 29987039. The results indicate that downstream of TrkC activation, most of the changes in gene expression are similar to those seen after TrkB activation. The results also show that exposure to sub-saturating concentrations of either BDNF or NT3 does not cause receptor downregulation as seen with saturating ligand concentrations and that the receptors can be re-activated.

2022-03-22 | E-MTAB-11566 | biostudies-arrayexpress

Phosphoproteomics of TrkA and TrkB signaling in SH-SY5Y neuroblastoma cells

Project description:Human neuroblastoma cells (SH-SY5Y) were engineered to have stable expression of either TrkA (NTRK1) or TrkB (NTRK2) receptors. The cells were pretreated with 0.5 μM Trametinib, 2.5 μM Gefitinib, and combination of 0.25 μM Trametinib and 1.25 μM Gefitinib. Stimulation of TrkA and TrkB-expressing SH-SY5Y cells was carried out 30 minutes following inhibitor addition, using 100 ng/mL of recombinant NGF (#450-01) and BDNF (#450-02), respectively (both from Peprotech). The stimulated and unstimulated controls are included.

2022-04-13 | PXD028943 | Pride

Rbfox1 up-regulation impairs BDNF-dependent hippocampal LTP by dysregulating TrkB isoform expression levels.

Project description:Brain Derived Neurotrophic Factor (BDNF) is a potent modulator of brain synaptic plasticity. Signaling defects caused by dysregulation of its NTrk2 (TrkB) kinase (TrkB.FL) and truncated receptors (TrkB.T1) have been linked to the pathophysiology of several neurological and neurodegenerative disorders. We found that upregulation of Rbfox1, an RNA binding protein associated with intellectual disability, epilepsy and autism, increases selectively hippocampal TrkB.T1 isoform expression. Physiologically, increased Rbfox1 impairs BDNF-dependent LTP which can be rescued by genetically restoring TrkB.T1 levels. RNA-seq analysis of hippocampi with upregulation of Rbfox1 in conjunction with the specific increase of TrkB.T1 isoform expression also shows that the genes affected by Rbfox1 gain of function are surprisingly different from those influenced by Rbfox1 deletion. These findings not only identify TrkB as a major target of Rbfox1 pathophysiology but also suggest that gain or loss of function of Rbfox1 regulate different genetic landscapes.

2019-08-24 | GSE136253 | GEO

RNA-seq of human neurons derived from H9 embryonic stem cell lines treated with BDNF, TrkB agonist ZEB 85 or NT4 against untreated controls

Project description:As a result of a large number of in vitro as well as in vivo experiments with rodents, brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB are now widely appreciated to play major roles in brain function. There is also a growing appreciation that decreased BDNF signalling may be a significant component in a wide range of brain dysfunction in humans based on the discovery of mutations and polymorphisms in the corresponding genes. Human neurons generated in vitro had been shown to be responsive to TrkB phosphorylation upon treatment with BNDF, TrkB agonist ZEB85, the related factor neurotrophin-4 (NT4). In order to compare the transcriptional changes upon treatment with the three TrkB ligands RNA-seq analysis was deployed. Cultures had been treated in triplicates with BDNF, ZEB85 or NT4 for 30 minutes, 2 hours, 12 hours and 24 hours, while non treated controls were lysed at each time-point.

2018-07-13 | E-MTAB-6975 | biostudies-arrayexpress

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