UNASSIGNED: Hypertrophic scars (HS) are dermal diseases characterized by excessive fibroblast proliferation and collagen deposition following burns or trauma. While Tenascin-C (TNC)\'s role in promoting visceral fibrosis has been established, its impact on skin tissue fibrosis remains unclear. This study aims to investigate the effects of TNC on HS.
UNASSIGNED: RNA sequence and IHC techniques were used to examine the upregulation of TNC gene in human hypertrophic scar tissue compared to normal tissues. Knockdown of TNC in Human skin fibroblasts (HFF-1) cells was achieved, and expression of Col1 and Col3 was evaluated using qPCR. Sirius red collagen staining assessed impact on total collagen content and ECM deposition. Effects on cell proliferation and migration were investigated through cck-8 and cell scratch experiments. Lentivirus infection was used to knock out TNC, and resulting samples were injected into ear wound of rabbits. Effects of TNC knockout on ear scar formation were measured using digital morphology, ultrasound, SEI, H&E, and Masson trichrome methods.
UNASSIGNED: Cell experiments: downregulation of TNC decreased Col1 and Col3 expression, leading to reduced collagen production and extracellular matrix deposition. It did not affect HFF-1 cell proliferation and migration. Animal experiments: TNC knockdown promoted wound healing and reduced collagen deposition in rabbit ears.
UNASSIGNED: This study suggests that knocking down TNC inhibits collagen formation and extracellular matrix deposition, thereby inhibiting hypertrophic scar formation. Therefore, TNC can be considered a potential biomarker for HS formation and may offer promising treatment strategies for clinical management of hypertrophic scars.

BACKGROUND: This study aims to analyze the pathogenic gene in a Chinese family with non-syndromic hearing loss and identify a novel mutation site in the TNC gene.
METHODS: A five-generation Chinese family from Anhui Province, presenting with autosomal dominant non-syndromic hearing loss, was recruited for this study. By analyzing the family history, conducting clinical examinations, and performing genetic analysis, we have thoroughly investigated potential pathogenic factors in this family. The peripheral blood samples were obtained from 20 family members, and the pathogenic genes were identified through whole exome sequencing. Subsequently, the mutation of gene locus was confirmed using Sanger sequencing. The conservation of TNC mutation sites was assessed using Clustal Omega software. We utilized functional prediction software including dbscSNV_AdaBoost, dbscSNV_RandomForest, NNSplice, NetGene2, and Mutation Taster to accurately predict the pathogenicity of these mutations. Furthermore, exon deletions were validated through RT-PCR analysis.
RESULTS: The family exhibited autosomal dominant, progressive, post-lingual, non-syndromic hearing loss. A novel synonymous variant (c.5247A > T, p.Gly1749Gly) in TNC was identified in affected members. This variant is situated at the exon-intron junction boundary towards the end of exon 18. Notably, glycine residue at position 1749 is highly conserved across various species. Bioinformatics analysis indicates that this synonymous mutation leads to the disruption of the 5\' end donor splicing site in the 18th intron of the TNC gene. Meanwhile, verification experiments have demonstrated that this synonymous mutation disrupts the splicing process of exon 18, leading to complete exon 18 skipping and direct splicing between exons 17 and 19.
CONCLUSIONS: This novel splice-altering variant (c.5247A > T, p.Gly1749Gly) in exon 18 of the TNC gene disrupts normal gene splicing and causes hearing loss among HBD families.

BACKGROUND: Atrial Fibrillation (AF), a prevalent arrhythmic condition, is intricately associated with atrial fibrosis, a major pathological contributor. Central to the development of atrial fibrosis is myocardial inflammation. This study focuses on Atrial Natriuretic Peptide (ANP) and its role in mitigating atrial fibrosis, aiming to elucidate the specific mechanisms by which ANP exerts its effects, with an emphasis on fibroblast dynamics.
RESULTS: The study involved forty Sprague-Dawley rats, divided into four groups: control, Angiotensin II (Ang II), Ang II + ANP, and ANP only. The administration of 1 µg/kg/min Ang II was given to Ang II and Ang II + ANP groups, while both Ang II + ANP and ANP groups received 0.1 µg/kg/min ANP intravenously for a duration of 14 days. Cardiac fibroblasts were used for in vitro validation of the proposed mechanisms. The study observed that rats in the Ang II and Ang II + ANP groups showed an increase in blood pressure and a decrease in body weight, more pronounced in the Ang II group. Diastolic dysfunction, a characteristic of the Ang II group, was alleviated by ANP. Additionally, ANP significantly reduced Ang II-induced atrial fibrosis, myofibroblast proliferation, collagen overexpression, macrophage infiltration, and the elevated expression of Interleukin 6 (IL-6) and Tenascin-C (TN-C). Transcriptomic sequencing indicated enhanced PI3K/Akt signaling in the Ang II group. Furthermore, in vitro studies showed that ANP, along with the PI3K inhibitor LY294002, effectively reduced PI3K/Akt pathway activation and the expression of TN-C, collagen-I, and collagen-III, which were induced by Ang II.
CONCLUSIONS: The study demonstrates ANP\'s potential in inhibiting myocardial inflammation and reducing atrial fibrosis. Notably, ANP\'s effect in countering atrial fibrosis seems to be mediated through the suppression of the Ang II-induced PI3K/Akt-Tenascin-C signaling pathway. These insights enhance our understanding of AF pathogenesis and position ANP as a potential therapeutic agent for treating atrial fibrosis.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease characterized by retarded alveolarization. Tenascin-C (TN-C), an extracellular matrix glycoprotein and soluble molecule, is involved in tissue morphogenesis. In the present study, we demonstrated that the level of TN-C in lung tissues was greater in a mouse model of BPD induced by 85% oxygen. TN-C deficiency, however, impaired alveolarization in the hyperoxia-induced BPD model. In contrast, a functional TN-C blocking antibody ameliorated alveolar dysplasia in BPD-like mice. Mechanistically, hyperoxia increased the soluble TN-C (sTN-C) released from respiratory epithelial cells. On one hand, low-dose sTN-C promoted lung epithelial cell proliferation and migration, which was mediated by ICAM-1. On the other hand, high-dose sTN-C hindered the proliferation and migration of epithelial cells. Overall, this study revealed that TN-C plays a dual role in lung alveolarization and that TN-C may be a target in BPD therapy.

Fractures are frequent and severe musculoskeletal injuries. This study aimed to investigate the function of tenascin-C (TNC) in regulating chondrogenic during fracture healing and elucidate the underlying molecular mechanisms. A well-established femur fracture model in male C57BL/6J mice was used to transect the middle diaphysis of the femur. To identify the essential role of TNC, shTNC lentiviruses or TNC protein were administered in the animal model. Micro-CT analysis, histologic analysis, immunostaining assays, and gene expression analysis were employed to investigate the effect of TNC during fracture healing. An in vitro mesenchymal stem cell culture system was developed to investigate the role and molecular mechanism of TNC in regulating chondrogenesis. TNC expression was induced at the inflammatory phase and peaked at the cartilaginous callus phase during fracture healing. Knockdown of TNC expression in callus results in decreased callus formation and impaired fracture healing. Conversely, administration of exogenous TNC promoted chondrogenic differentiation, cartilage template formation and ultimately improved fracture healing. Both the Hedgehog and Hippo signaling pathways were found to be involved in the pro-chondrogenic function of TNC. Our observations demonstrate that TNC is a crucial factor responsible for endochondral ossification in fracture healing and provide a potential therapeutic strategy for promoting fracture healing.

Human satellite cells (HuSCs) have been deemed to be the potential cure to treat muscular atrophy diseases such as Duchenne muscular dystrophy. However, the clinical trials of HuSCs were restricted to the inadequacy of donors because of that freshly isolated HuSCs quickly lost the Pax7 expression and myogenesis capacity in vivo after a few days of culture. Here we found that oleanic acid, a kind of triterpenoid endowed with diverse biological functions with treatment potential, could efficiently promote HuSCs proliferation. The HuSCs cultured in the medium supplement with oleanic acid could maintain a high expression level of Pax7 and retain the ability to differentiate into myotubes as well as facilitate muscle regeneration in injured muscles of recipient mice. We further revealed that Tenascin-C acts as the core mechanism to activate the EGFR signaling pathway followed by HuSCs proliferation. Taken together, our data provide an efficient method to expand functional HuSCs and a novel mechanism that controls HuSCs proliferation, which sheds light on the HuSCs-based therapy to treat muscle diseases.

UNASSIGNED: To assess the predictive value of tenascin-C (TN-C) for intravenous immunoglobulin (IVIG) non-responsiveness and coronary artery lesions (CALs) development at the acute stage of Kawasaki disease, and to build novel scoring systems for identifying IVIG non-responsiveness and CALs.
UNASSIGNED: A total of 261 patients in acute-stage Kawasaki disease were included. Serum samples before IVIG initiation were collected and TN-C expression levels were measured using an enzyme-linked immunosorbent assay. In addition to TN-C, another fifteen clinical and laboratory parameters collected before treatment were compared between IVIG responsive and non-responsive groups, and between groups with and without CALs. Multiple logistic regression analyses were performed to construct new scoring systems for the prediction of IVIG non-responsiveness and CALs development.
UNASSIGNED: IVIG non-responsive group (n = 51) had significantly higher TN-C level compared to IVIG responsive group (n = 210) (15.44 vs. 12.38 IU/L, P < 0.001). A novel scoring system composed of TN-C, total bilirubin, serum sodium and albumin was established to predict IVIG non-responsiveness. Patients with a total score ≥ 2 points were classified as high-risk cases. With the sensitivity of 78.4% and specificity of 73.8%, the efficiency of our scoring system for predicting IVIG non-responsiveness was comparable to the Kobayashi system. Consistently, the group developing CALs at the acute stage (n = 42) had significantly higher TN-C level compared to the group without CALs (n = 219) (19.76 vs. 12.10 IU/L, P < 0.001). A new scoring system showed that patients with elevated TN-C, platelet count ≥ 450 × 109/L, and delayed initial infusion of IVIG had a higher risk of developing CALs. Individuals with a total score ≥ 3 points were classified as high-risk cases. The sensitivity and specificity of the novel simple system for predicting CALs development were 83.3% and 74.0%, respectively, yielding a better efficiency than the Harada score.
UNASSIGNED: Elevated TN-C appeared to be an independent risk factor for both IVIG non-responsiveness and CALs in Chinese children with KD. Our scoring systems containing TN-C is simple and efficient in the early identification of high-risk KD cases that could benefit from more individualized medications.

(1) Background: Injury repair is a complex physiological process in which multiple cells and molecules are involved. Tenascin-C (TNC), an extracellular matrix (ECM) glycoprotein, is essential for angiogenesis during wound healing. This study aims to provide a comprehensive review of the dynamic changes and functions of TNC throughout tissue regeneration and to present an up-to-date synthesis of the body of knowledge pointing to multiple mechanisms of TNC at different restoration stages. (2) Methods: A review of the PubMed database was performed to include all studies describing the pathological processes of damage restoration and the role, structure, expression, and function of TNC in post-injury treatment; (3) Results: In this review, we first introduced the construction and expression signature of TNC. Then, the role of TNC during the process of damage restoration was introduced. We highlight the temporal heterogeneity of TNC levels at different restoration stages. Furthermore, we are surprised to find that post-injury angiogenesis is dynamically consistent with changes in TNC. Finally, we discuss the strategies for TNC in post-injury treatment. (4) Conclusions: The dynamic expression of TNC has a significant impact on angiogenesis and healing wounds and counters many negative aspects of poorly healing wounds, such as excessive inflammation, ischemia, scarring, and wound infection.

Cardiac fibrosis is a common pathology in the advanced stage of cardiovascular diseases, which leads to cardiac systolic and diastolic dysfunction. It is important to prevent cardiac fibrosis during myocardial injury. The transcription factor Prrx1 is involved in cancer-associated fibrosis and other organ fibrosis. However, the role and mechanism of Prrx1 in cardiac fibrosis deserves further exploration. We identified that overexpressed Prrx1 promoted the proliferation and migration of cardiac fibroblasts, and transform cardiac fibroblasts to myofibroblasts in vitro. We demonstrated that the expression of Prrx1 is upregulated in TGF-β1-treated fibroblasts. And silencing Prrx1 could attenuate cardiac fibrosis induced by TGF-β1 in vitro. In addition, a Twist1-paired-related homeobox 1 (Prrx1)-tenascin-C (TNC) positive feedback loop (PFL) combined with Twist1, Prrx1, and TNC activated fibroblasts, which was the mechanism the Prrx1 in cardiac fibrosis. In conclusion, our findings showed that the deficiency of Prrx1 attenuated cardiac fibrosis in vitro and reveal a novel Twist1-Prrx1-TNC PFL in the regulation of cardiac fibrosis.

UNASSIGNED: Tenascin-C (TNC) has been found to abnormally express in myocardial ischemia/reperfusion injury (MI/RI), but its effect on cardiomyocytes apoptosis is unknown and is worthy of investigation.
UNASSIGNED: H9C2 cells were given hypoxia/reoxygenation (H/R) treatment to obtain the replica of MI/RI in vitro. The effect of H/R on viability, apoptosis and inflammation was studied by CCK-8 assay, flow cytometry, mitochondrial membrane potential (MMP) and Ca2+ measurements as well as enzyme linked immunosorbent assay. We applied bioinformatics analysis and luciferase reporter assay to screened and validated TNC-targeting miR-495-3p which was then mechanistically investigated by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. With the assistance of cell transfection, rescue assays were conducted.
UNASSIGNED: H9C2 cells showed diminished viability, accelerated apoptosis, elevated tumour necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β), and TNC overexpression in response to H/R induction, while silencing of TNC partially reversed the effect of H/R treatment on the H9C2 cells. TNC silencing reduced Ca2+ level and enhanced MMP level in the H/R-stimulated cells. MiR-495-3p targeted TNC and showed a low expression in the H/R-stimulated cells. The expression of TNC was negatively regulated by miR-495-3p. Inhibition of miR-495-3p repressed viability and MMP level, and facilitated apoptosis and levels of Ca2+, TNF-α and IL-1β in the H/R-stimulated cells. The effect of TNC silencing and miR-495-3p depletion on H/R-induced cardiomyocyte injury was mutually reversed in vitro.
UNASSIGNED: MiR-495-3p targeted TNC to regulate the apoptosis and inflammation of cardiomyocytes in H/R induction, which was associated with Ca2+ overload.