The development of early human lymphatic vessels as characterized by lymphatic endothelial markers.

Lymphatic vessel development studies in mice and zebrafish models have demonstrated that lymphatic endothelial cells (LECs) predominantly differentiate from venous endothelial cells via the expression of the transcription factor Prox1. However, LECs can also be generated from undifferentiated mesoderm, suggesting potential diversity in their precursor cell origins depending on the organ or anatomical location. Despite these advances, recapitulating human lymphatic malformations in animal models has been difficult, and considering lymphatic vasculature function varies widely between species, analysis of development directly in humans is needed. Here, we examined early lymphatic development in humans by analyzing the histology of 31 embryos and three 9-week-old fetuses. We found that human embryonic cardinal veins, which converged to form initial lymph sacs, produce Prox1-expressing LECs. Furthermore, we describe the lymphatic vessel development in various organs and observe organ-specific differences. These characterizations of the early development of human lymphatic vessels should help to better understand the evolution and phylogenetic relationships of lymphatic systems, and their roles in human disease.

Cardiovascular Magnetic Resonance Radiomics to Identify Components of the Extracellular Matrix in Dilated Cardiomyopathy.

BACKGROUND: Current cardiovascular magnetic resonance sequences cannot discriminate between different myocardial extracellular space (ECSs), including collagen, noncollagen, and inflammation. We sought to investigate whether cardiovascular magnetic resonance radiomics analysis can distinguish between noncollagen and inflammation from collagen in dilated cardiomyopathy. METHODS: We identified data from 132 patients with dilated cardiomyopathy scheduled for an invasive septal biopsy who underwent cardiovascular magnetic resonance at 3 T. Cardiovascular magnetic resonance imaging protocol included native and postcontrast T1 mapping and late gadolinium enhancement (LGE). Radiomic features were computed from the midseptal myocardium, near the biopsy region, on native T1, extracellular volume (ECV) map, and LGE images. Principal component analysis was used to reduce the number of radiomic features to 5 principal radiomics. Moreover, a correlation analysis was conducted to identify radiomic features exhibiting a strong correlation (r>0.9) with the 5 principal radiomics. Biopsy samples were used to quantify ECS, myocardial fibrosis, and inflammation. RESULTS: Four histopathological phenotypes were identified: low collagen (n=20), noncollagenous ECS expansion (n=49), mild to moderate collagenous ECS expansion (n=42), and severe collagenous ECS expansion (n=21). Noncollagenous expansion was associated with the highest risk of myocardial inflammation (65%). Although native T1 and ECV provided high diagnostic performance in differentiating severe fibrosis (C statistic, 0.90 and 0.90, respectively), their performance in differentiating between noncollagen and mild to moderate collagenous expansion decreased (C statistic: 0.59 and 0.55, respectively). Integration of ECV principal radiomics provided better discrimination and reclassification between noncollagen and mild to moderate collagen (C statistic, 0.79; net reclassification index, 0.83 [95% CI, 0.45-1.22]; P<0.001). There was a similar trend in the addition of native T1 principal radiomics (C statistic, 0.75; net reclassification index, 0.93 [95% CI, 0.56-1.29]; P<0.001) and LGE principal radiomics (C statistic, 0.74; net reclassification index, 0.59 [95% CI, 0.19-0.98]; P=0.004). Five radiomic features per sequence were identified with correlation analysis. They showed a similar improvement in performance for differentiating between noncollagen and mild to moderate collagen (native T1, ECV, LGE C statistic, 0.75, 0.77, and 0.71, respectively). These improvements remained significant when confined to a single radiomic feature (native T1, ECV, LGE C statistic, 0.71, 0.70, and 0.64, respectively). CONCLUSIONS: Radiomic features extracted from native T1, ECV, and LGE provide incremental information that improves our capability to discriminate noncollagenous expansion from mild to moderate collagen and could be useful for detecting subtle chronic inflammation in patients with dilated cardiomyopathy.

Expression of Tenascin-C Is Upregulated in the Early Stages of Radiation Pneumonitis/Fibrosis in a Novel Mouse Model.

The lung is a major dose-limiting organ for radiation therapy (RT) for cancer in the thoracic region, and the clarification of radiation-induced lung damage (RILD) is important. However, there have been few reports containing a detailed comparison of radiographic images with the pathological findings of radiation pneumonitis (RP)/radiation fibrosis (RF). We recently reported the upregulated expression of tenascin-C (TNC), an inflammation-associated extracellular matrix molecule, in surgically resected lung tissue, and elevated serum levels were elevated in a RILD patient. Therefore, we have developed a novel mouse model of partial lung irradiation and studied it with special attention paid to the computed tomography (CT) images and immunohistological findings. The right lungs of mice (BALB/c) were irradiated locally at 30 Gy/1fr, and the following two groups were created. In Group 1, sequential CT was performed to confirm the time-dependent changes in RILD. In Group 2, the CT images and histopathological findings of the lung were compared. RP findings were detected histologically at 16 weeks after irradiation; they were also observed on the CT images from 20 weeks. The immunostaining of TNC was observed before the appearance of RP on the CT images. The findings suggest that TNC could be an inflammatory marker preceding lung fibrosis.

Computational model captures cardiac growth in hypertensive pregnancies and in the postpartum period.

Heart growth in the pregnant patient helps maintain cardiovascular function while supporting the growing fetus. However, in some cases, the cardiovascular demand of pregnancy can trigger life-threatening conditions, including hypertensive disorders of pregnancy and peripartum cardiomyopathy. The mechanisms that control heart growth throughout pregnancy are unclear, and treating these diseases remains elusive. We previously developed a computational model that accounts for hormonal and hemodynamic interactions throughout pregnancy and demonstrated its ability to capture realistic cardiac growth in normal rat pregnancy. In this study, we evaluated whether this model could capture heart growth beyond normal pregnancy. After further validation of our normal pregnancy predictions, we tested our model predictions of three rat studies of hypertensive pregnancies. We next simulated the postpartum period and examined the impact of lactation on cardiac growth in rats. We demonstrate that our multiscale model can capture cardiac growth associated with new-onset hypertension during pregnancy and lactation status in the postpartum period. We conclude by elaborating on the potential clinical utility of our model in the future.NEW & NOTEWORTHY Our multiscale model predicts appropriate heart growth beyond normal pregnancy, including elevated heart weights in rats with induced hypertension during pregnancy and in lactating mice and decreased heart weight in nonlactating mice. Our model captures distinct mechanisms that result in similar organ-level growth, highlighting its potential to distinguish healthy from diseased pregnancy-induced growth.

The extracellular matrix fibulin 7 maintains epidermal stem cell heterogeneity during skin aging.

Tissue stem cells (SCs) divide infrequently as a protective mechanism against internal and external stresses associated with aging. Here, we demonstrate that slow- and fast-cycling SCs in the mouse skin epidermis undergo distinct aging processes. Two years of lineage tracing reveals that Dlx1+ slow-cycling clones expand into the fast-cycling SC territory, while the number of Slc1a3+ fast-cycling clones gradually declines. Transcriptome analysis further indicate that the molecular properties of each SC population are altered with age. Mice lacking fibulin 7, an extracellular matrix (ECM) protein, show early impairments resembling epidermal SC aging, such as the loss of fast-cycling clones, delayed wound healing, and increased expression of inflammation- and differentiation-related genes. Fibulin 7 interacts with structural ECM and matricellular proteins, and the overexpression of fibulin 7 in primary keratinocytes results in slower proliferation and suppresses differentiation. These results suggest that fibulin 7 plays a crucial role in maintaining tissue resilience and epidermal SC heterogeneity during skin aging.

Histopathological findings of pericarditis in a patient with multisystem inflammatory syndrome in children associated with COVID-19: A case report.

Multisystem inflammatory syndrome in children (MIS-C), which is associated with the novel coronavirus disease 2019 (COVID-19), has been described as an inflammatory complication of exposure to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It carries a risk of serious and lethal complications, including cardiogenic shock. Here, we report the pathological findings of the pericardium in a 10-year-old child with MIS-C, who developed pericarditis-induced cardiac tamponade. In the patient's pericardium, the numbers of infiltrating CD68+ macrophages; CD3+ , CD4+ , and CD8+ T cells; and myeloperoxidase+ granulocytes were increased, although the number of CD20+ B cells was not. These findings provide a clue to understanding the pathophysiology of MIS-C.

Improved Antitumor Effect of NK Cells Activated by Neutrophils in a Bone Marrow Transplant Model.

The licensing process mediated by inhibitory receptors of the Ly49 C-type lectin superfamily that recognizes self-major histocompatibility complex (MHC) class I in mice is essential for the proper antitumor function of natural killer (NK) cells. Several models for NK cell licensing can be exploited for adoptive immunotherapy for cancer. However, the appropriate adoptive transfer setting to induce efficient graft versus tumor/leukemia effects remains elusive, especially after hematopoietic stem cell transplantation (HSCT). In our previous experiment, we showed that intraperitoneal neutrophil administration with their corresponding NK receptor ligand-activated NK cells using congenic mice without HSCT. In this experiment, we demonstrate enhanced antitumor effects of licensed NK cells induced by weekly intraperitoneal injections of irradiated neutrophil-enriched peripheral blood mononuclear cells (PBMNCs) in recipient mice bearing lymphoma. Bone marrow transplantation was performed using BALB/c mice (H-2d) as the recipient and B10 mice (H-2b) as the donor. The tumor was A20, a BALB/c-derived lymphoma cell line, which was injected subcutaneously into the recipient at the same time as the HSCT. Acute graft versus host disease was not exacerbated in this murine MHC class I mismatched HSCT setting. The intraperitoneal injection of PBMNCs activated a transient licensing of NK subsets expressed Ly49G2, its corresponding NK receptor ligand to H-2d, and reduced A20 tumor growth in the recipient after HSCT. Pathological examination revealed that increased donor-oriented NK1.1+NK cells migrated into the recipient tumors, depending on neutrophil counts in the administered PBMNCs. Collectively, our data reveal a pivotal role of neutrophils in promoting NK cell effector functions and adoptive immunotherapy for cancer.

Tenascin-C in Tissue Repair after Myocardial Infarction in Humans.

Adverse ventricular remodeling after myocardial infarction (MI) is progressive ventricular dilatation associated with heart failure for weeks or months and is currently regarded as the most critical sequela of MI. It is explained by inadequate tissue repair due to dysregulated inflammation during the acute stage; however, its pathophysiology remains unclear. Tenascin-C (TNC), an original member of the matricellular protein family, is highly up-regulated in the acute stage after MI, and a high peak in its serum level predicts an increased risk of adverse ventricular remodeling in the chronic stage. Experimental TNC-deficient or -overexpressing mouse models have suggested the diverse functions of TNC, particularly its pro-inflammatory effects on macrophages. The present study investigated the roles of TNC during human myocardial repair. We initially categorized the healing process into four phases: inflammatory, granulation, fibrogenic, and scar phases. We then immunohistochemically examined human autopsy samples at the different stages after MI and performed detailed mapping of TNC in human myocardial repair with a focus on lymphangiogenesis, the role of which has recently been attracting increasing attention as a mechanism to resolve inflammation. The direct effects of TNC on human lymphatic endothelial cells were also assessed by RNA sequencing. The results obtained support the potential roles of TNC in the regulation of macrophages, sprouting angiogenesis, the recruitment of myofibroblasts, and the early formation of collagen fibrils during the inflammatory phase to the early granulation phase of human MI. Lymphangiogenesis was observed after the expression of TNC was down-regulated. In vitro results revealed that TNC modestly down-regulated genes related to nuclear division, cell division, and cell migration in lymphatic endothelial cells, suggesting its inhibitory effects on lymphatic endothelial cells. The present results indicate that TNC induces prolonged over-inflammation by suppressing lymphangiogenesis, which may be one of the mechanisms underlying adverse post-infarct remodeling.

Different Types of Myocardial Injury due to the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Omicron Variant.

Coronavirus disease 2019 (COVID-19) associated myocardial injury was caused by various mechanisms. We herein describe 2 cases presenting different types of myocardial injury due to Omicron variant. In both patients, diffuse reduced left ventricular (LV) wall motion in transthoracic echocardiography, electrocardiographic abnormality, and elevated myocardial enzymes were demonstrated. In addition, cardiovascular magnetic resonance (CMR) findings fulfilled the 2018 Lake Louise Criteria (LLC) for myocarditis. However, histological findings in 1 patient showed inflammatory cell infiltration with myocyte degeneration, while those in the other showed interstitial edema without inflammatory cell infiltration. Histological findings were crucial for a differential diagnosis of myocardial injury due to Omicron variant.

Myocardial T-Lymphocytes as a Prognostic Risk-Stratifying Marker of Dilated Cardiomyopathy　- Results of the Multicenter Registry to Investigate Inflammatory Cell Infiltration in Dilated Cardiomyopathy in Tissues of Endomyocardial Biopsy (INDICATE Study).

BACKGROUND: Dilated cardiomyopathy (DCM) associated with inflammation is diagnosed by endomyocardial biopsy; patients with this have a poorer prognosis than patients without inflammation. To date, standard diagnostic criteria have not been established.Methods and Results: This study analyzed clinical records and endomyocardial biopsy samples of 261 patients with DCM (201 males, median left ventricular ejection fraction; 28%) from 8 institutions in a multicenter retrospective study. Based on the European Society of Cardiology criteria and CD3 (T-lymphocytes) and CD68 (macrophages) immunohistochemistry, 48% of patients were categorized as having inflammatory DCM. For risk-stratification, we divided patients into 3 groups using Akaike Information Criterion/log-rank tests, which can determine multiple cut-off points: CD3+-Low, <13/mm2(n=178, 68%); CD3+-Moderate, 13-24/mm2(n=58, 22%); and CD3+-High, ≥24/mm2(n=25, 10%). The survival curves for cardiac death or left ventricular assist device implantation differed significantly among the 3 groups (10-year survival rates: CD3+-Low: 83.4%; CD3+-Moderate: 68.4%; CD3+-High: 21.1%; Log-rank P<0.001). Multivariate Cox analysis revealed CD3+count as a potent independent predictive factor for survival (fully adjusted hazard ratio: CD3+-High: 5.70, P<0.001; CD3+-Moderate: 2.64, P<0.01). CD3+-High was also associated with poor left ventricular functional and morphological recovery at short-term follow up. CONCLUSIONS: Myocardial CD3+T-lymphocyte infiltration has a significant prognostic impact in DCM and a 3-tiered risk-stratification model could be helpful to refine patient categorization.

Aryl Hydrocarbon Receptor Directly Regulates VTCN1 Gene Expression in MCF-7 Cells.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the toxicity of dioxins and polycyclic aromatic hydrocarbons. Recent studies have suggested that AhR is involved in cancer immunity. In the present study, we examined whether AhR regulates the expression of immune checkpoint genes in breast cancer cells. We discovered that the mRNA expression of V-set domain containing T cell activation inhibitor 1 (VTCN1) that negatively regulates T cell immunity was upregulated by AhR agonists in breast cancer cell lines, MCF-7 and T47D. Furthermore, AhR knockout or knockdown experiments clearly demonstrated that upregulation of VTCN1 gene expression by 3-methylcholanthrene was AhR dependent. Luciferase reporter and chromatin immunoprecipitation assays revealed that this upregulation of VTCN1 gene expression was induced by the recruitment of AhR to the AhR responsive element in the VTCN1 gene promoter in MCF-7 cells. Taken together, AhR directly regulates VTCN1 gene expression in MCF-7 cells.

Clinical significance of chronic myocarditis: systematic review and meta-analysis.

Chronic myocarditis is a prolonged inflammatory condition in the myocardium and its histological manifestation is defined by the presence of an inflammatory infiltrate. Chronic myocarditis has not been well known and its treatment of chronic myocarditis has not been established. Primary outcome of this study was to assess the efficacy of immunomodulatory treatment in addition to conventional treatment, and secondary outcomes were to clarity the prognosis of natural history of chronic myocarditis and incidence of chronic myocarditis in patients with dilated cardiomyopathy (DCM). We searched for studies in Medline, Embase, Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi published between January 1946 and June 2020. Sixteen studies met the inclusion criteria. A meta-analysis revealed that patients receiving immunomodulatory treatment showed an improvement in left ventricular ejection fraction after immunomodulatory treatment compared to the control group (hazard ratio, 16.65; confidence interval, 4.55-28.74; p = 0.007). Five-year survival rate of the patients with inflammatory DCM (iDCM) and DCM was 52.7-70.3% and 51.9-91.1%, respectively. Moreover, 51.5%-62.7% of patients with DCM met the criteria of iDCM. Our systematic review revealed that patients with chronic myocarditis had poor prognosis and immunomodulatory treatment was significantly effective in addition to conventional treatment.

The Pathogenesis of Cardiac Fibrosis: A Review of Recent Progress.

Fibrosis is defined as the excessive deposition of extracellular matrix (ECM) proteins in the interstitium. It is an essential pathological response to chronic inflammation. ECM protein deposition is initially protective and is critical for wound healing and tissue regeneration. However, pathological cardiac remodeling in excessive and continuous tissue damage with subsequent ECM deposition results in a distorted organ architecture and significantly impacts cardiac function. In this review, we summarized and discussed the histologic features of cardiac fibrosis with the signaling factors that control it. We evaluated the origin and characteristic markers of cardiac fibroblasts. We also discussed lymphatic vessels, which have become more important in recent years to improve cardiac fibrosis.

Peripartum Mid-Ventricular-Type Takotsubo Cardiomyopathy After Cesarean Delivery.

There are several causes of heart failure during pregnancy and the peripartum period, which include peripartum cardiomyopathy, Takotsubo cardiomyopathy or stress cardiomyopathy, exacerbation of a preexisting cardiomyopathy, and acute myocarditis. It is important to determine the cause of the heart failure as the medical treatment may be different based on the diagnosis. However, it has been sometimes challenging to diagnose the cause because of the limited diagnostic tools, especially in pregnant women. Cardiac MRI can characterize myocardial injury and can be used to track the changes in myocardial tissue. We herein report a 35-year-old woman diagnosed with peripartum mid-ventricular-type Takotsubo cardiomyopathy, who was referred to our hospital due to worsening dyspnea the day after cesarean delivery. On admission, electrocardiography showed sinus tachycardia and poor progression of R waves in the precordial leads. Bedside echocardiography revealed severe hypokinesis in the mid- and apical left ventricle (LV) with a LV ejection fraction of 20%. Cardiac catheterization showed normal coronary arteries, and myocardial biopsy revealed contraction band necrosis. On acute phase (Day 4), cardiac MRI showed prolonged native T1 and T2, and severe hypokinesis and decreased regional longitudinal peak strain in the mid-anterior LV wall. During the 1st week, precordial ST fluctuation was observed, and LV wall motion had gradually recovered. Repeat cardiac MRI revealed normalized LV wall motion and shortened values for global native T1 and T2. Thus, she was diagnosed with peripartum Takotsubo cardiomyopathy. Serial cardiac MRI may be able to differentiate Takotsubo cardiomyopathy during pregnancy and the peripartum period from other preexisting cardiomyopathies.

Hepatitis B Core-Related Antigen to Indicate High Viral Load: Systematic Review and Meta-Analysis of 10,397 Individual Participants.

BACKGROUND & AIMS: To eliminate hepatitis B virus (HBV) infection, scale-up of testing and treatment in resource-limited countries is crucial. However, access to nucleic acid testing to quantify HBV DNA, an essential test to examine treatment eligibility, remains severely limited. We assessed the performance of a novel immunoassay, HBV core-related antigen (HBcrAg), as a low-cost (less than US $15/assay) alternative to nucleic acid testing to indicate clinically important high viremia in chronic HBV patients infected with different genotypes. METHODS: We searched Medline, Embase, Scopus, and Web of Science databases through June 27, 2018. Three reviewers independently selected studies measuring HBV DNA and HBcrAg in the same blood samples. We contacted authors to provide individual participant data (IPD). We randomly allocated each IPD to a derivation or validation cohort. We applied optimal HBcrAg cut-off values derived from the derivation set to the validation set to estimate sensitivity/specificity. RESULTS: Of 74 eligible studies, IPD were obtained successfully for 60 studies (81%). Meta-analysis included 5591 IPD without antiviral therapy and 4806 treated with antivirals. In untreated patients, the pooled area under the receiver operating characteristic curve and optimal cut-off values were as follows: 0.88 (95% CI, 0.83-0.94) and 3.6 log U/mL to diagnose HBV DNA level of 2000 IU/mL or greater; and 0.96 (95% CI, 0.94-0.98) and 5.3 log U/mL for 200,000 IU/mL or greater, respectively. In the validation set, the sensitivity and specificity were 85.2% and 84.7% to diagnose HBV DNA level of 2000 IU/mL or greater, and 91.8% and 90.5% for 200,000 IU/mL or greater, respectively. The performance did not vary by HBV genotypes. In patients treated with anti-HBV therapy the correlation between HBcrAg and HBV DNA was poor. CONCLUSIONS: HBcrAg might be a useful serologic marker to indicate clinically important high viremia in treatment-naïve, HBV-infected patients.

Tenascin-C Induces Phenotypic Changes in Fibroblasts to Myofibroblasts with High Contractility through the Integrin αvß1/Transforming Growth Factor ß/SMAD Signaling Axis in Human Breast Cancer.

Tenascin-C (TNC) is strongly expressed by fibroblasts and cancer cells in breast cancer. To assess the effects of TNC on stromal formation, we examined phenotypic changes in human mammary fibroblasts treated with TNC. The addition of TNC significantly up-regulated α-smooth muscle actin (α-SMA) and calponin. TNC increased the number of α-SMA- and/or calponin-positive cells with well-developed stress fibers in immunofluorescence, which enhanced contractile ability in collagen gel contraction. The treatment with TNC also significantly up-regulated its own synthesis. Double immunofluorescence of human breast cancer tissues showed α-SMA- and/or calponin-positive myofibroblasts in the TNC-deposited stroma. Among several receptors for TNC, the protein levels of the αv and ß1 integrin subunits were significantly increased after the treatment. Immunofluorescence showed the augmented colocalization of αv and ß1 at focal adhesions. Immunoprecipitation using an anti-αv antibody revealed a significant increase in coprecipitated ß1 with TNC in lysates. The knockdown of αv and ß1 suppressed the up-regulation of α-SMA and calponin. The addition of TNC induced the phosphorylation of SMAD2/3, whereas SB-505124 and SIS3 blocked myofibroblast differentiation. Therefore, TNC enhances its own synthesis by forming a positive feedback loop and increases integrin αvß1 heterodimer levels to activate transforming growth factor-ß signaling, which is followed by a change to highly contractile myofibroblasts. TNC may essentially contribute to the stiffer stromal formation characteristic of breast cancer tissues.

Tenascin-C in Heart Diseases-The Role of Inflammation.

Tenascin-C (TNC) is a large extracellular matrix (ECM) glycoprotein and an original member of the matricellular protein family. TNC is transiently expressed in the heart during embryonic development, but is rarely detected in normal adults; however, its expression is strongly up-regulated with inflammation. Although neither TNC-knockout nor -overexpressing mice show a distinct phenotype, disease models using genetically engineered mice combined with in vitro experiments have revealed multiple significant roles for TNC in responses to injury and myocardial repair, particularly in the regulation of inflammation. In most cases, TNC appears to deteriorate adverse ventricular remodeling by aggravating inflammation/fibrosis. Furthermore, accumulating clinical evidence has shown that high TNC levels predict adverse ventricular remodeling and a poor prognosis in patients with various heart diseases. Since the importance of inflammation has attracted attention in the pathophysiology of heart diseases, this review will focus on the roles of TNC in various types of inflammatory reactions, such as myocardial infarction, hypertensive fibrosis, myocarditis caused by viral infection or autoimmunity, and dilated cardiomyopathy. The utility of TNC as a biomarker for the stratification of myocardial disease conditions and the selection of appropriate therapies will also be discussed from a clinical viewpoint.

A New Mouse Model of Chronic Myocarditis Induced by Recombinant Bacille Calmette-Guèrin Expressing a T-Cell Epitope of Cardiac Myosin Heavy Chain-α.

Dilated cardiomyopathy (DCM) is a potentially lethal disorder characterized by progressive impairment of cardiac function. Chronic myocarditis has long been hypothesized to be one of the causes of DCM. However, owing to the lack of suitable animal models of chronic myocarditis, its pathophysiology remains unclear. Here, we report a novel mouse model of chronic myocarditis induced by recombinant bacille Calmette-Guérin (rBCG) expressing a CD4+ T-cell epitope of cardiac myosin heavy chain-α (rBCG-MyHCα). Mice immunized with rBCG-MyHCα developed chronic myocarditis, and echocardiography revealed dilation and impaired contraction of ventricles, similar to those observed in human DCM. In the heart, CD62L-CD4+ T cells were increased and produced significant amounts of IFN-γ and IL-17 in response to cardiac myosin. Adoptive transfer of CD62L-CD4+ T cells induced myocarditis in the recipient mice, which indicated that CD62L-CD4+ T cells were the effector cells in this model. rBCG-MyHCα-infected dendritic cells produced proinflammatory cytokines and induced MyHCα-specific T-cell proliferation and Th1 and Th17 polarization. This novel chronic myocarditis mouse model may allow the identification of the central pathophysiological and immunological processes involved in the progression to DCM.

Tenascin-C in cardiac disease: a sophisticated controller of inflammation, repair, and fibrosis.

Tenascin-C (TNC) is a large extracellular matrix glycoprotein classified as a matricellular protein that is generally upregulated at high levels during physiological and pathological tissue remodeling and is involved in important biological signaling pathways. In the heart, TNC is transiently expressed at several important steps during embryonic development and is sparsely detected in normal adult heart but is re-expressed in a spatiotemporally restricted manner under pathological conditions associated with inflammation, such as myocardial infarction, hypertensive cardiac fibrosis, myocarditis, dilated cardiomyopathy, and Kawasaki disease. Despite its characteristic and spatiotemporally restricted expression, TNC knockout mice develop a grossly normal phenotype. However, various disease models using TNC null mice combined with in vitro experiments have revealed many important functions for TNC and multiple molecular cascades that control cellular responses in inflammation, tissue repair, and even myocardial regeneration. TNC has context-dependent diverse functions and, thus, may exert both harmful and beneficial effects in damaged hearts. However, TNC appears to deteriorate adverse ventricular remodeling by proinflammatory and profibrotic effects in most cases. Its specific expression also makes TNC a feasible diagnostic biomarker and target for molecular imaging to assess inflammation in the heart. Several preclinical studies have shown the utility of TNC as a biomarker for assessing the prognosis of patients and selecting appropriate therapy, particularly for inflammatory heart diseases.

Tenascin-C in brain injuries and edema after subarachnoid hemorrhage: Findings from basic and clinical studies.

Subarachnoid hemorrhage (SAH) by a rupture of cerebral aneurysms remains the most devastating cerebrovascular disease. Early brain injury (EBI) is increasingly recognized to be the primary determinant for poor outcomes, and also considered to cause delayed cerebral ischemia (DCI) after SAH. Both clinical and experimental literatures emphasize the impact of global cerebral edema in EBI as negative prognostic and direct pathological factors. The nature of the global cerebral edema is a mixture of cytotoxic and vasogenic edema, both of which may be caused by post-SAH induction of tenascin-C (TNC) that is an inducible, non-structural, secreted and multifunctional matricellular protein. Experimental SAH induces TNC in brain parenchyma in rats and mice. TNC knockout suppressed EBI in terms of brain edema, blood-brain barrier disruption, neuronal apoptosis and neuroinflammation, associated with the inhibition of post-SAH activation of mitogen-activated protein kinases and nuclear factor-kappa B in mice. In a clinical setting, more severe SAH increases more TNC in cerebrospinal fluid and peripheral blood, which could be a surrogate marker of EBI and predict DCI development and outcomes. In addition, cilostazol, a selective inhibitor of phosphodiesterase type III that is a clinically available anti-platelet agent and is known to suppress TNC induction, dose-dependently inhibited delayed cerebral infarction and improved outcomes in a pilot clinical study. Thus, further studies may facilitate application of TNC as biomarkers for non-invasive diagnosis or assessment of EBI and DCI, and lead to development of a molecular target drug against TNC, contributing to the improvement of post-SAH outcomes.