Explore the vast range of titles available.

The synaptic transmission in the mammalian brain is not limited to the interplay between the pre- and the postsynapse of neurons, but involves also astrocytes as well as extracellular matrix (ECM) molecules. Glycoproteins, proteoglycans and hyaluronic acid of the ECM pervade the pericellular environment and condense to special superstructures termed perineuronal nets (PNN) that surround a subpopulation of CNS neurons. The present study focuses on the analysis of PNNs in a quadruple knockout mouse deficient for the ECM molecules tenascin-C (TnC), tenascin-R (TnR), neurocan and brevican. Here, we analysed the proportion of excitatory and inhibitory synapses and performed electrophysiological recordings of the spontaneous neuronal network activity of hippocampal neurons in vitro . While we found an increase in the number of excitatory synaptic molecules in the quadruple knockout cultures, the number of inhibitory synaptic molecules was significantly reduced. This observation was complemented with an enhancement of the neuronal network activity level. The in vivo analysis of PNNs in the hippocampus of the quadruple knockout mouse revealed a reduction of PNN size and complexity in the CA2 region. In addition, a microarray analysis of the postnatal day (P) 21 hippocampus was performed unravelling an altered gene expression in the quadruple knockout hippocampus.

Pattern recognition underpins innate immunity; the accurate identification of danger, including infection, injury, or tumor, is key to an appropriately targeted immune response. Pathogen detection is increasingly well defined mechanistically, but the discrimination of endogenous inflammatory triggers remains unclear. Tenascin-C, a matrix protein induced upon tissue damage and expressed by tumors, activates toll-like receptor 4 (TLR4)-mediated sterile inflammation. Here we map three sites within tenascin-C that directly and cooperatively interact with TLR4. We also identify a conserved inflammatory epitope in related proteins from diverse families, and demonstrate that its presence targets molecules for TLR detection, while its absence enables escape of innate immune surveillance. These data reveal a unique molecular code that defines endogenous proteins as inflammatory stimuli by marking them for recognition by TLRs. Although detection of pathogens by pattern recognition receptors is increasingly well defined, recognition of endogenous triggers remains poorly understood. By examining the interface between tenascin-C and TLR4, the authors identify a molecular code that identifies endogenous proteins as inflammatory stimuli.

The factors responsible for maintaining persistent organ fibrosis in systemic sclerosis (SSc) are not known but emerging evidence implicates toll-like receptors (TLRs) in the pathogenesis of SSc. Here we show the expression, mechanism of action and pathogenic role of endogenous TLR activators in skin from patients with SSc, skin fibroblasts, and in mouse models of organ fibrosis. Levels of tenascin-C are elevated in SSc skin biopsy samples, and serum and SSc fibroblasts, and in fibrotic skin tissues from mice. Exogenous tenascin-C stimulates collagen gene expression and myofibroblast transformation via TLR4 signalling. Mice lacking tenascin-C show attenuation of skin and lung fibrosis, and accelerated fibrosis resolution. These results identify tenascin-C as an endogenous danger signal that is upregulated in SSc and drives TLR4-dependent fibroblast activation, and by its persistence impedes fibrosis resolution. Disrupting this fibrosis amplification loop might be a viable strategy for the treatment of SSc. Systemic sclerosis (SSc) is a fibrotic disease affecting multiple organs. Here the authors use patient samples plus mouse studies to show a central role for tenascin C as a TLR4 activator responsible for persistence of fibrosis in the context of SSc and SSc-like disease.

In conditions such as neurodegenerative diseases, posttraumatic stress disorder (PTSD), addiction and spinal cord injuries, restricted synaptic plasticity hinders the formation of new neuronal connections, preventing the compensation and treatment of adverse behaviors. Perineuronal nets (PNNs) significantly restrict synaptic plasticity by inhibiting synapse formation. The digestion of PNNs has been associated with short-term cognitive improvements and reduced long-term memory, offering potential therapeutic benefits in PTSD. This study investigates the correlation between PNNs and fear memory processes in extracellular matrix (ECM) mutant mice, particularly focusing on the amygdala-medial prefrontal cortex (mPFC) circuit, which is crucial for fear memory generation and maintenance. Fear conditioning was conducted on mice lacking four key ECM-molecules: brevican, neurocan, tenascin-C and tenascin-R (4x KO). These mice exhibited severe impairments in memory consolidation, as evident by their inability to retrieve previously learned fear memories, coupled with reduced PNN density and disturbed synaptic integrity along their PNNs. Additionally, changes in neural activity in the basolateral amygdala (BL) and reductions in VGAT + synaptic puncta in the amygdala-mPFC circuit were observed. In contrast, tenascin single KOs showed intact fear behavior and memory compared to their control groups. Impaired fear memory consolidation can be advantageous in certain conditions, such as PTSD, making the 4x KO mice an intriguing model for future fear conditioning studies and highlighting brevican, neurocan, Tnc, and Tnr as compelling targets for further investigation. This study underscores the significance of ECM regulation for synaptic organization and the potential of PNN modulation as a therapeutic target for fear memory-related conditions.

Dermal fibroblasts and cutaneous nerves are important players in skin diseases, while their reciprocal roles during skin inflammation have not been characterized. Here we identify an inflammation-induced subset of papillary fibroblasts that promotes aberrant neurite outgrowth and psoriasiform skin inflammation by secreting the extracellular matrix protein tenascin-C (TNC). Single-cell analysis of fibroblast lineages reveals a Tnc + papillary fibroblast subset with pro-axonogenesis and neuro-regulation transcriptomic hallmarks. TNC overexpression in fibroblasts boosts neurite outgrowth in co-cultured neurons, while fibroblast-specific TNC ablation suppresses hyperinnervation and alleviates skin inflammation in male mice modeling psoriasis. Dermal γδT cells, the main producers of type 17 pathogenic cytokines, frequently contact nerve fibers in mouse psoriasiform lesions and are likely modulated by postsynaptic signals. Overall, our results highlight the role of an inflammation-responsive fibroblast subset in facilitating neuro-immune synapse formation and suggest potential avenues for future therapeutic research. Local cues for hyperinnervation in chronic skin diseases are not fully understood. Here, the authors show that a distinct subset of dermal papillary fibroblasts promote neurite outgrowth and facilitate neuron-immune interactions through extracellular matrix remodeling in a mouse model of psoriasis

The pathophysiology of keloid formation is not yet understood, so the identification of biomarkers for kelod can be one step towards designing new targeting therapies which will improve outcomes for patients with keloids or at risk of developing keloids. In this study, we performed single-cell RNA sequencing analysis, weighted co-expression network analysis, and differential expression analysis of keloids based on public databases. And 3 RNA sequencing data from keloid patients in our center were used for validation. Besides, we performed QRT-PCR on keloid tissue and adjacent normal tissues from 16 patients for further verification. We identified the sensitive biomarker of keloid: Tenascin-C (TNC). Then, Pseudotime analysis found that the expression level of TNC decreased first, then stabilized and finally increased with fibroblast differentiation, suggesting that TNC may play an potential role in fibroblast differentiation. In addition, there were differences in the infiltration level of macrophages M0 between the TNC-high group and the TNC-low group. Macrophages M0 had a higher infiltration level in low TNC- group (P<0.05). Our results can provide a new idea for the diagnosis and treatment of keloid.

Super-enhancers (SEs) are associated with key genes that control cellular state and cell identity. Endoplasmic reticulum stress (ERS) regulates epithelial-mesenchymal transformation (EMT). However, whether SEs are involved in ERS-related activation of EMT in hepatocellular carcinoma (HCC) is unknown. In this study, we identified 17 ERS-related SEs by comparing ERS-HCC cells with untreated control cells using ChIP-seq and RNA-seq. CRISPR-Cas9 and RT-qPCR identified CAMP responsive element binding protein 5 (CREB5) as a key target of ERS-related SE. Analyses of TCGA datasets and tissue arrays showed that CREB5 mRNA and protein expression levels were higher in liver cancer tissues than in paired normal tissues. In addition, overexpression of CREB5 was associated with poor prognosis and an aggressive phenotype in patients with HCC. We also found that activation of ERS enhanced the expression of CREB5, and upregulation of CREB5 significantly increased cell proliferation, migration, and invasion, and promoted EMT, but inhibited apoptosis. More importantly, ERS activation increased the expression of several EMT markers by modulating the expression of CREB5. Mechanistically, CREB5 upregulates the transcription of tenascin-C (TNC) by directly binding to its promoter region, thereby promoting EMT in liver cancer cells. In summary, our findings suggest that ERS activation promotes EMT in liver cancer cells via SE-mediated upregulation of the CREB5/TNC pathway. This result provides a new direction for uncovering how ERS regulates EMT and a foundation for preventing the progression of EMT in HCC.

Background Markers of stromal activation at future metastatic sites may have prognostic value and may allow clinicians to identify and abolish the pre-metastatic niche to prevent metastasis. In this study, we evaluate tenascin-C as a marker of pre-metastatic niche formation in bladder cancer patient lymph nodes. Methods Tenascin-C expression in benign lymph nodes was compared between metastatic ( n  = 20) and non-metastatic ( n  = 27) patients with muscle-invasive bladder cancer. Urinary extracellular vesicle (EV) cytokine levels were measured with an antibody array to examine potential correlation with lymph node inflammation. The ability of bladder cancer EVs to activate primary bladder fibroblasts was assessed in vitro. Results Lymph node tenascin-C expression was elevated in metastatic patients vs . non-metastatic patients, and high expression was associated with worse survival. Urinary EVs contained four cytokines that were positively correlated with lymph node tenascin-C expression. Bladder cancer EVs induced tenascin-C expression in fibroblasts in an NF-κB-dependent manner. Conclusions Tenascin-C expression in regional lymph nodes may be a good predictor of bladder cancer metastasis and an appropriate imaging target. It may be possible to interrupt pre-metastatic niche formation by targeting EV-borne tumour cytokines or by targeting tenascin-C directly.

Tenascin C (TNC) is an element of the extracellular matrix (ECM) of various tissues, including the skin, and is involved in modulating ECM integrity and cell physiology. Although skin aging is apparently associated with changes in the ECM, little is known about the role of TNC in skin aging. In this study, we found that the Tnc mRNA level was significantly reduced in the skin tissues of aged mice compared with young mice, consistent with reduced TNC protein expression in aged human skin. TNC-large (TNC-L; 330-kDa) and -small (TNC-S; 240-kDa) polypeptides were observed in conditional media from primary dermal fibroblasts. Both recombinant TNC polypeptides, corresponding to TNC-L and TNC-S, increased the expression of type I collagen and reduced the expression of matrix metalloproteinase-1 in fibroblasts. Treatment of fibroblasts with a recombinant TNC polypeptide, corresponding to TNC-L, induced phosphorylation of SMAD2 and SMAD3. TNC increased the level of transforming growth factor-β1 (TGF-β1) mRNA and upregulated the expression of type I collagen by activating the TGF-β signaling pathway. In addition, TNC also promoted the expression of type I collagen in fibroblasts embedded in a three-dimensional collagen matrix. Our findings suggest that TNC contributes to the integrity of ECM in young skin and to prevention of skin aging.

Tenascin-C (TNC) is an extracellular matrix (ECM) glycoprotein that plays an important role in cell proliferation, migration, and tumour invasion in various cancers. TNC is one of the main protein overexpressed in breast cancer, indicating a role for this ECM molecule in cancer pathology. In this study we have evaluated the TNC loss-off-function in breast cancer cells. In our approach, we used dsRNA sharing sequence homology with TNC mRNA, called ATN-RNA. We present the data showing the effects of ATN-RNA in MDA-MB-231 cells both in monolayer and three-dimensional culture. Cells treated with ATN-RNA were analyzed for phenotypic alterations in proliferation, migration, adhesion, cell cycle, multi-caspase activation and the involvement in epithelial to mesenchymal transition (EMT) processes. As complementary analysis the oncogenomic portals were used to assess the clinical implication of TNC expression on breast cancer patient's survival, showing the TNC overexpression associated with a poor survival outcome. Our approach applied first in brain tumors and then in breast cancer cell lines reveals that ATN-RNA significantly diminishes the cell proliferation, migration and additionally, reverses the mesenchymal cells phenotype to the epithelial one. Thus, TNC could be considered as the universal target in different types of tumors, where TNC overexpression is associated with poor prognosis.