Pubblicazioni recenti - cardiac fibroblast

• GHR gene transcript heterogeneity may explain phenotypic variability in GHR pseudoexon (6?) patients.
  Endocr Connect

  2020 Feb;():. doi: 10.1530/EC-20-0026.
  
  Chatterjee Sumana, Cottrell Emily, Rose Stephen J, Mushtaq Talat, Maharaj Avinash Vickram, Williams Jack, Savage Martin O, Metherell Louise A, Storr Hl,
  
  Abstract
  
  OBJECTIVES:
  The homozygous GH receptor (GHR) pseudoexon (6?) mutation leads to growth hormone insensitivity (GHI) with clinical and biochemical heterogeneity. We investigated whether transcript heterogeneity (6?-GHR to WT-GHR transcript ratio) and/or concurrent defects in other short stature (SS) genes contribute to this.
  
  METHODS:
  6?-GHR and WT-GHR mRNA transcripts of 4 6? patient (height SDS -4.2 to -3.1) and 1 control fibroblasts were investigated by RT-PCR. Transcripts were quantified by qRT-PCR and delta delta CT analysis and compared using ANOVA with Bonferroni correction. In eleven 6? patients, 40 genes known to cause GHI/SS were analysed by targeted next generation sequencing.
  
  RESULTS:
  RT-PCR confirmed 6?-GHR transcript in the 6? patients but not control. 6?-GHR transcript levels were comparable in patients 1 and 3 but significantly different among all other patients. The mean 6?:WT transcript ratios ranged from 29-71:1 for patients 1-4 and correlated negatively with height SDS (R=-0.85; p<0.001). Eight deleterious variants in 6 genes were detected but the number of gene hits did not correlate with the degree of SS in individual 6? patients.
  
  CONCLUSION:
  Variable amounts of 6?- and WT-GHR transcripts were identified in 6? patients but no 6? transcript was present in the control. Higher 6?:WT GHR transcript ratio correlated with SS severity and may explain the phenotypic variability. Analysis of known SS genes suggested that phenotypic variation is independent of the genetic background. This is the first report of transcript heterogeneity producing a spectrum of clinical phenotypes in different individuals harbouring an identical homozygous genetic mutation.
  
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• Phosphorylation of GATA4 at serine-105 is required for left ventricular remodelling process in angiotensin-II - induced hypertension in rats.
  Basic Clin Pharmacol Toxicol

  2020 Feb;():. doi: 10.1111/bcpt.13398.
  
  Jurado Acosta Alicia, Rysä Jaana, Szabo Zoltan, Moilanen Anne-Mari, Serpi Raisa, Ruskoaho Heikki,
  
  Abstract
  
  In this study, we investigated whether local intramyocardial GATA4 overexpression affects the left ventricular (LV) remodelling process and the importance of phosphorylation at serine-105 (S105) for the actions of GATA4 in an angiotensin II (AngII)-induced hypertension rat model. Adenoviral constructs overexpressing wild type GATA4 or GATA4 mutated at S105 were delivered into the anterior LV free wall. AngII (33.3 µg x kg x h ) was administered via subcutaneously implanted minipumps. Cardiac function and structure were examined by echocardiography, followed by histological immunostainings of LV sections and gene expression measurements by RT-qPCR. The effects of GATA4 on cultured neonatal rat ventricular fibroblasts were evaluated. In AngII-induced hypertension, GATA4 overexpression repressed fibrotic gene expression, reversed the hypertrophic adult-to-foetal isoform switch of myofibrillar genes and prevented apoptosis, whereas histological fibrosis was not affected. Overexpression of GATA4 mutated at S105 resulted in LV chamber dilatation, cardiac dysfunction and had minor effects on expression of myocardial remodelling genes. Fibrotic gene expression in cardiac fibroblasts was differently affected by overexpression of wild type or mutated GATA4. Our results indicate that GATA4 reduces AngII-induced responses by interfering with pro-fibrotic and hypertrophic gene expressions. GATA4 actions on LV remodelling and fibroblasts are dependent on phosphorylation site S105.
  
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• Two novel cases further expand the phenotype of TOR1AIP1-associated nuclear envelopathies.
  Hum Genet

  2020 Feb;():. doi: 10.1007/s00439-019-02105-6.
  
  Lessel Ivana, Chen Mei-Jan, Lüttgen Sabine, Arndt Florian, Fuchs Sigrid, Meien Stefanie, Thiele Holger, Jones Julie R, Shaw Brandon R, Crossman David K, Nürnberg Peter, Korf Bruce R, Kubisch Christian, Lessel Davor,
  
  Abstract
  
  Biallelic variants in TOR1AIP1, encoding the integral nuclear membrane protein LAP1 (lamina-associated polypeptide 1) with two functional isoforms LAP1B and LAP1C, have initially been linked to muscular dystrophies with variable cardiac and neurological impairment. Furthermore, a recurrent homozygous nonsense alteration, resulting in loss of both LAP1 isoforms, was identified in seven likely related individuals affected by multisystem anomalies with progeroid-like appearance and lethality within the 1st decade of life. Here, we have identified compound heterozygosity in TOR1AIP1 affecting both LAP1 isoforms in two unrelated individuals affected by congenital bilateral hearing loss, ventricular septal defect, bilateral cataracts, mild to moderate developmental delay, microcephaly, mandibular hypoplasia, short stature, progressive muscular atrophy, joint contractures and severe chronic heart failure, with much longer survival. Cellular characterization of primary fibroblasts of one affected individual revealed absence of both LAP1B and LAP1C, constitutively low lamin A/C levels, aberrant nuclear morphology including nuclear cytoplasmic channels, and premature senescence, comparable to findings in other progeroid forms of nuclear envelopathies. We additionally observed an abnormal activation of the extracellular signal-regulated kinase 1/2 (ERK 1/2). Ectopic expression of wild-type TOR1AIP1 mitigated these cellular phenotypes, providing further evidence for the causal role of identified genetic variants. Altogether, we thus further expand the TOR1AIP1-associated phenotype by identifying individuals with biallelic loss-of-function variants who survived beyond the 1st decade of life and reveal novel molecular consequences underlying the TOR1AIP1-associated disorders.
  
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• Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TWEAK)/Fibroblast Growth Factor-Inducible 14 (Fn14) Axis in Cardiovascular Diseases: Progress and Challenges.
  Cells

  2020 Feb;9(2):. doi: E405.
  
  Méndez-Barbero Nerea, Gutiérrez-Muñoz Carmen, Blázquez-Serra Rafael, Martín-Ventura Jose L, Blanco-Colio Luis M,
  
  Abstract
  
  Cardiovascular diseases (CVD) are the leading cause of mortality in Western countries. CVD include several pathologies, such as coronary artery disease, stroke, peripheral artery disease, and aortic aneurysm, among others. All of them are characterized by a pathological vascular remodeling in which inflammation plays a key role. Interaction between different members of the tumor necrosis factor superfamily and their cognate receptors induce several biological actions that may participate in CVD. The cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its functional receptor, fibroblast growth factor-inducible 14 (Fn14), are abundantly expressed during pathological cardiovascular remodeling. The TWEAK/Fn14 axis controls a variety of cellular functions, such as proliferation, differentiation, and apoptosis, and has several biological functions, such as inflammation and fibrosis that are linked to CVD. It has been demonstrated that persistent TWEAK/Fn14 activation is involved in both vessel and heart remodeling associated with acute and chronic CVD. In this review, we summarized the role of the TWEAK/Fn14 axis during pathological cardiovascular remodeling, highlighting the cellular components and the signaling pathways that are involved in these processes.
  
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• GPCR-induced YAP activation sensitizes fibroblasts to profibrotic activity of TGF?1.
  PLoS One

  2020 ;15(2):e0228195. doi: 10.1371/journal.pone.0228195.
  
  Zmajkovicova Katarina, Bauer Yasmina, Menyhart Katalin, Schnoebelen Marie, Freti Diego, Boucher Maxime, Renault Bérengère, Studer Rolf, Birker-Robaczewska Magdalena, Klenk Axel, Nayler Oliver, Gatfield John,
  
  Abstract
  
  Tissue fibrosis is a pathological condition characterized by uncontrolled fibroblast activation that ultimately leads to organ failure. The TGF?1 pathway, one of the major players in establishment of the disease phenotype, is dependent on the transcriptional co-activators YAP/TAZ. We were interested whether fibroblasts can be sensitized to TGF?1 by activation of the GPCR/YAP/TAZ axis and whether this mechanism explains the profibrotic properties of diverse GPCR ligands. We found that LPA, S1P and thrombin cooperate in human dermal fibroblasts with TGF?1 to induce extracellular matrix synthesis, myofibroblast marker expression and cytokine secretion. Whole genome expression profiling identified a YAP/TAZ signature behind the synergistic profibrotic effects of LPA and TGF?1. LPA, S1P and thrombin stimulation led to activation of the Rho-YAP axis, an increase of nuclear YAP-Smad2 complexes and enhanced expression of profibrotic YAP/Smad2-target genes. More generally, dermal, cardiac and lung fibroblast responses to TGF?1 could be enhanced by increasing YAP nuclear levels (with GPCR ligands LPA, S1P, thrombin or Rho activator) and inhibited by decreasing nuclear YAP (with Rho inhibitor, forskolin, latrunculin B or 2-deoxy-glucose). Thus, we present here a conceptually interesting finding that fibroblast responses to TGF?1 can be predicted based on the nuclear levels of YAP and modulated by stimuli/treatments that change YAP nuclear levels. Our study contributes to better understanding of fibrosis as a complex interplay of signalling pathways and proposes YAP/TAZ as promising targets in the treatment of fibrosis.
  
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• Facile Method for Fabrication of Meter-Long Multifunctional Hydrogel Fibers with Controllable Biophysical and Biochemical Features.
  ACS Appl Mater Interfaces

  2020 Feb;():. doi: 10.1021/acsami.9b23063.
  
  Mirani Bahram, Pagan Erik, Shojaei Shahla, Dabiri Seyed Mohammad Hossein, Savoji Houman, Mehrali Mehdi, Sam Mahshid, Alsaif Jehad, Bhiladvala Rustom B, Dolatshahi-Pirouz Alireza, Radisic Milica, Akbari Mohsen,
  
  Abstract
  
  Hydrogel structures with microscale morphological features have extensive application in tissue engineering owing to their capacity to induce desired cellular behavior. Herein, we describe a novel biofabrication method for fabrication of grooved solid and hollow hydrogel fibers with control over their cross-sectional shape, surface morphology, porosity, and material composition. These fibers were further configured into three-dimensional structures using textile technologies such as weaving, braiding, and embroidering methods. Additionally, the capacity of these fibers to integrate various biochemical and biophysical cues was shown via incorporating drug-loaded microspheres, conductive materials, and magnetic particles, extending their application to smart drug delivery, wearable or implantable medical devices, and soft robotics. The efficacy of the grooved fibers to induce cellular alignment was evaluated on various cell types including myoblasts, cardiomyocytes, cardiac fibroblasts, and glioma cells. In particular, these fibers were shown to induce controlled myogenic differentiation and morphological changes, depending on their groove size, in C2C12 myoblasts.
  
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• Bioreactor With Electrically Deformable Curved Membranes for Mechanical Stimulation of Cell Cultures.
  Front Bioeng Biotechnol

  2020 ;8():22. doi: 10.3389/fbioe.2020.00022.
  
  Costa Joana, Ghilardi Michele, Mamone Virginia, Ferrari Vincenzo, Busfield James J C, Ahluwalia Arti, Carpi Federico,
  
  Abstract
  
  Physiologically relevant models of stretchable biological tissues, such as muscle, lung, cardiac and gastro-intestinal tissues, should mimic the mechanical cues which cells are exposed to in their dynamic microenvironment . In particular, in order to mimic the mechanical stimulation of tissues in a physiologically relevant manner, cell stretching is often desirable on surfaces with dynamically controllable curvature. Here, we present a device that can deform cell culture membranes without the current need for external pneumatic/fluidic or electrical motors, which typically make the systems bulky and difficult to operate. We describe a modular device that uses elastomeric membranes, which can intrinsically be deformed by electrical means, producing a dynamically tuneable curvature. This approach leads to compact, self-contained, lightweight and versatile bioreactors, not requiring any additional mechanical equipment. This was obtained via a special type of dielectric elastomer actuator. The structure, operation and performance of early prototypes are described, showing preliminary evidence on their ability to induce changes on the spatial arrangement of the cytoskeleton of fibroblasts dynamically stretched for 8 h.
  
  Copyright © 2020 Costa, Ghilardi, Mamone, Ferrari, Busfield, Ahluwalia and Carpi.
  
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• Secreted Phospholipase A-IIA Modulates Transdifferentiation of Cardiac Fibroblast through EGFR Transactivation: An Inflammation-Fibrosis Link.
  Cells

  2020 Feb;9(2):. doi: E396.
  
  Martin Ruben, Gutierrez Beatriz, Cordova Claudia, Roman Alberto San, Alvarez Yolanda, Hernandez Marita, Cachofeiro Victoria, Nieto Maria L,
  
  Abstract
  
  Secreted phospholipase A-IIA (sPLA-IIA) is a pro-inflammatory protein associated with cardiovascular disorders, whose functions and underlying mechanisms in cardiac remodelling are still under investigation. We herein study the role of sPLA-IIA in cardiac fibroblast (CFs)-to-myofibroblast differentiation and fibrosis, two major features involved in cardiac remodelling, and also explore potential mechanisms involved. In a mice model of dilated cardiomyopathy (DCM) after autoimmune myocarditis, serum and cardiac sPLA-IIA protein expression were found to be increased, together with elevated cardiac levels of the cross-linking enzyme lysyl oxidase (LOX) and reactive oxygen species (ROS) accumulation. Exogenous sPLA-IIA treatment induced proliferation and differentiation of adult rat CFs. Molecular studies demonstrated that sPLA-IIA promoted Src phosphorylation, shedding of the membrane-anchored heparin-binding EGF-like growth factor (HB-EGF) ectodomain and EGFR phosphorylation, which triggered phosphorylation of ERK, P70S6K and rS6. This was also accompanied by an up-regulated expression of the bone morphogenic protein (BMP)-1, LOX and collagen I. ROS accumulation were also found to be increased in sPLA-IIA-treated CFs. The presence of inhibitors of the Src/ADAMs-dependent HB-EGF shedding/EGFR pathway abolished the CF phenotype induced by sPLA-IIA. In conclusion, sPLA-IIA may promote myofibroblast differentiation through its ability to modulate EGFR transactivation and signalling as key mechanisms that underlie its biological and pro-fibrotic effects.
  
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• Cardiac Expression of Factor X Mediates Cardiac Hypertrophy and Fibrosis in Pressure Overload.
  JACC Basic Transl Sci

  2020 Jan;5(1):69-83. doi: 10.1016/j.jacbts.2019.10.006.
  
  Guo Xinji, Kolpakov Mikhail A, Hooshdaran Bahman, Schappell William, Wang Tao, Eguchi Satoru, Elliott Katherine J, Tilley Douglas G, Rao A Koneti, Andrade-Gordon Patricia, Bunce Matthew, Madhu Chintala, Houser Steven R, Sabri Abdelkarim,
  
  Abstract
  
  Activated factor X is a key component of the coagulation cascade, but whether it directly regulates pathological cardiac remodeling is unclear. In mice subjected to pressure overload stress, cardiac factor X mRNA expression and activity increased concurrently with cardiac hypertrophy, fibrosis, inflammation and diastolic dysfunction, and responses blocked with a low coagulation-independent dose of rivaroxaban. In vitro, neurohormone stressors increased activated factor X expression in both cardiac myocytes and fibroblasts, resulting in activated factor X-mediated activation of protease-activated receptors and pro-hypertrophic and -fibrotic responses, respectively. Thus, inhibition of cardiac-expressed activated factor X could provide an effective therapy for the prevention of adverse cardiac remodeling in hypertensive patients.
  
  © 2020 The Authors.
  
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• The Effect of Cardiogenic Factors on Cardiac Mesenchymal Cell Anti-Fibrogenic Paracrine Signaling and Therapeutic Performance.
  Theranostics

  2020 ;10(4):1514-1530. doi: 10.7150/thno.41000.
  
  Heidel Justin S, Fischer Annalara G, Tang Xian-Liang, Sadri Ghazal, Wu Wen-Jian, Moisa Claudiu R, Stowers Heather, Sandella Neel, Wysoczynski Marcin, Uchida Shizuka, Moore Iv Joseph B,
  
  Abstract
  
  Intrinsic cardiogenic factor expression, a proxy for cardiomyogenic lineage commitment, may be an important determinant of donor cell cardiac reparative capacity in cell therapy applications; however, whether and how this contributes to their salutary effects remain largely ambiguous. : The current study examined the consequences of enhanced cardiogenic factor expression, via lentiviral delivery of GMT (GATA4, MEF2C, and TBX5), on cardiac mesenchymal cell (CMC) anti-fibrogenic paracrine signaling dynamics, , and cardiac reparative capacity, . Proteome cytokine array analyses and cardiac fibroblast activation assays were performed using conditioned medium derived from either GMT- or GFP control-transduced CMCs, to respectively assess cardiotrophic factor secretion and anti-fibrogenic paracrine signaling aptitude. : Relative to GFP controls, GMT CMCs exhibited enhanced secretion of cytokines implicated to function in pathways associated with matrix remodeling and collagen catabolism, and more ably impeded activated cardiac fibroblast Col1A1 synthesis . Following their delivery in a rat model of chronic ischemic cardiomyopathy, conventional echocardiography was unable to detect a therapeutic advantage with either CMC population; however, hemodynamic analyses identified a modest, yet calculable supplemental benefit in surrogate measures of global left ventricular contractility with GMT CMCs relative to GFP controls. This phenomenon was neither associated with a decrease in infarct size nor an increase in viable myocardium, but with only a marginal decrease in regional myocardial collagen deposition. : Overall, these results suggest that CMC cardiomyogenic lineage commitment biases cardiac repair and, further, that enhanced anti-fibrogenic paracrine signaling potency may underlie, in part, their improved therapeutic utility.
  
  © The author(s).
  
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• Fasting-induced FGF21 signaling activates hepatic autophagy and lipid degradation via JMJD3 histone demethylase.
  Nat Commun

  2020 Feb;11(1):807. doi: 10.1038/s41467-020-14384-z.
  
  Byun Sangwon, Seok Sunmi, Kim Young-Chae, Zhang Yang, Yau Peter, Iwamori Naoki, Xu H Eric, Ma Jian, Kemper Byron, Kemper Jongsook Kim,
  
  Abstract
  
  Autophagy is essential for cellular survival and energy homeostasis under nutrient deprivation. Despite the emerging importance of nuclear events in autophagy regulation, epigenetic control of autophagy gene transcription remains unclear. Here, we report fasting-induced Fibroblast Growth Factor-21 (FGF21) signaling activates hepatic autophagy and lipid degradation via Jumonji-D3 (JMJD3/KDM6B) histone demethylase. Upon FGF21 signaling, JMJD3 epigenetically upregulates global autophagy-network genes, including Tfeb, Atg7, Atgl, and Fgf21, through demethylation of histone H3K27-me3, resulting in autophagy-mediated lipid degradation. Mechanistically, phosphorylation of JMJD3 at Thr-1044 by FGF21 signal-activated PKA increases its nuclear localization and interaction with the nuclear receptor PPAR? to transcriptionally activate autophagy. Administration of FGF21 in obese mice improves defective autophagy and hepatosteatosis in a JMJD3-dependent manner. Remarkably, in non-alcoholic fatty liver disease patients, hepatic expression of JMJD3, ATG7, LC3, and ULK1 is substantially decreased. These findings demonstrate that FGF21-JMJD3 signaling epigenetically links nutrient deprivation with hepatic autophagy and lipid degradation in mammals.
  
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• Cardiac Fibroblast Diversity.
  Annu Rev Physiol

  2020 Feb;82():63-78. doi: 10.1146/annurev-physiol-021119-034527.
  
  Tallquist Michelle D,
  
  Abstract
  
  Cardiac fibrosis is a pathological condition that occurs after injury and during aging. Currently, there are limited means to effectively reduce or reverse fibrosis. Key to identifying methods for curbing excess deposition of extracellular matrix is a better understanding of the cardiac fibroblast, the cell responsible for collagen production. In recent years, the diversity and functions of these enigmatic cells have been gradually revealed. In this review, I outline current approaches for identifying and classifying cardiac fibroblasts. An emphasis is placed on new insights into the heterogeneity of these cells as determined by lineage tracing and single-cell sequencing in development, adult, and disease states. These recent advances in our understanding of the fibroblast provide a platform for future development of novel therapeutics to combat cardiac fibrosis.
  
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• MiR-216a accelerates proliferation and fibrogenesis via targeting PTEN and SMAD7 in human cardiac fibroblasts.
  Cardiovasc Diagn Ther

  2019 Dec;9(6):535-544. doi: 10.21037/cdt.2019.11.06.
  
  Tao Jinsong, Wang Jingyi, Li Chunyu, Wang Weiwei, Yu Hao, Liu Jinhui, Kong Xiangqing, Chen Yan,
  
  Abstract
  
  Background:
  Heart failure (HF) is a progressive disease with relatively poor prognosis and lacks effective therapy, and the discovery of dysregulated microRNAs (miRNAs) and their role in cardiac fibroblasts have provided a new avenue for elucidating the mechanism involved in HF.
  
  Methods:
  Two datasets of GSE53080 and GSE57338 were used to screen the miRNAs profiling and analysis the differentially expressed genes (DEGs) in HF. QRT-PCR was used to detect miR-216a between HF and healthy controls (HC). Cell counting kit-8 (CCK-8) assay and clonogenic assay were used to analyze the effect of proliferation and fibrogenesis. Then dual-luciferase activity assay and western blotting were used to confirm the key mechanism.
  
  Results:
  In this study, the results showed that miR-216a was significantly up-regulated in HF and over-expression of miR-216a promoted proliferation and enhanced the fibrogenesis in the human cardiac fibroblasts (HCF) cells. Phosphatase and tensin homolog (PTEN) and mothers against decapentaplegic homolog 7 (SMAD7) were both validated as the direct target genes of miR-216a, which were confirmed by the dual-luciferase reporter assay. MiR-216a decreased the expression of PTEN and SMAD7 leading to the activation of Akt/mTOR and TGF-?RI/Smad2 in the HCF cells, which might act as a promoter of cardiac fibrosis.
  
  Conclusions:
  Our study might provide a promising approach for the treatment of HF in the future.
  
  2019 Cardiovascular Diagnosis and Therapy. All rights reserved.
  
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• Cell-to-cell lactate shuttle operates in heart and is important in age-related heart failure.
  Aging (Albany NY)

  2020 Feb;12():. doi: 10.18632/aging.102818.
  
  Gizak Agnieszka, McCubrey James A, Rakus Dariusz,
  
  Abstract
  
  Recent studies have revealed a resemblance of a HIF-regulated heart and brain glycolytic profiles prompting the hypothesis that the classical cell-to-cell lactate shuttle observed between astrocytes and neurons operates also in heart - between cardiac fibroblasts and cardiomyocytes. Here, we demonstrate that co-culturing of cardiomyocytes with cardiac fibroblasts leads to orchestrated changes in expression and/or localization pattern of glucose metabolism enzymes and lactate transport proteins in both cell types. These changes are regulated by paracrine signaling using microvesicle-packed and soluble factors released to the culture medium and, taken together, they concur with the cardiac lactate shuttle hypothesis. The results presented here show that similarity of heart and brain proteomes demonstrated earlier extend to physiological level and provide a theoretical rationale for designing novel therapeutic strategies for treatment of cardiomyopathies resulting from disruption of the maturation of cardiac metabolic pathways, and of heart failure associated with metabolic complications and age-related heart failure linked with extracellular matrix deposition and hypoxia.
  
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• Single-cell revolution unveils the mysteries of the regenerative mammalian digit tip.
  Dev Biol

  2020 Feb;():. doi: S0012-1606(20)30045-2.
  
  Riquelme-Guzmán Camilo, Contreras Osvaldo,
  
  Abstract
  
  The digit tip is an exciting model for studying regeneration in mammals, but the precise mechanisms and the populations of cells involved in the formation and remodeling of the blastema remain unknown. In an exciting new work, Storer et al. take advantage of single-cell RNAseq combined with Pdgfra+ ?lineage-tracing to open the way into the enigmatic world of mammalian tissue regeneration.
  
  Copyright © 2020 Elsevier Inc. All rights reserved.
  
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• Downregulation of miR-96 suppresses the profibrogenic functions of cardiac fibroblasts induced by angiotensin II and attenuates atrial fibrosis by upregulating KLF13.
  Hum Cell

  2020 Feb;():. doi: 10.1007/s13577-020-00326-w.
  
  Su Lijie, Yao Yili, Song Wei,
  
  Abstract
  
  Atrial fibrosis is a hallmark of structural remodeling in atrial fibrillation (AF). MicroRNA-96 (miR-96) has been reported to be associated with pulmonary fibrosis and hepatic fibrosis. Nevertheless, the role of miR-96 in atrial fibrosis is still unclear. In our study, we showed that miR-96 is upregulated in human atrial tissues from AF patients and positively correlates with collagen I and collagen III levels. Knockdown of miR-96 reduced angiotensin II (Ang-II)-induced cardiac-fibroblast proliferation, migration, and collagen production, whereas ectopic expression of miR-96 yielded opposite results. Furthermore, we demonstrated that miR-96 represses KLF13 expression, subsequently promoting Ang-II-induced proliferation, migration, and collagen production in murine cardiac fibroblasts. Moreover, we observed that the knockdown of miR-96 attenuated the Ang-II-induced atrial fibrosis in a mouse model of AF. All the findings point to a potential target for the prevention or treatment of atrial fibrosis.
  
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• Pro-fibrotic effect of oxidized LDL in cardiac myofibroblasts.
  Biochem Biophys Res Commun

  2020 Feb;():. doi: S0006-291X(20)30241-2.
  
  Villa Monica, Cerda-Opazo Paulina, Jimenez-Gallegos Danica, Garrido-Moreno Valeria, Chiong Mario, Quest Andrew Fg, Toledo Jorge, Garcia Lorena,
  
  Abstract
  
  Inflammatory signals associated with cardiac diseases trigger trans-differentiation of cardiac fibroblasts to cardiac myofibroblasts. Cardiac myofibroblasts are the main cell type involved in the development of cardiac fibrosis, a diffuse and disproportionate accumulation of collagen in the myocardium. Although the role of the scavenger like-lectin receptor LOX-1 was previously investigated in cardiac fibroblasts and fibrosis, the involvement of the LOX-1 ligand -oxidized low-density lipoprotein (oxLDL)- on cardiac myofibroblast function still remains unexplored. In the present work, we investigated the effect of oxLDL/LOX-1 on fibrotic markers and cardiac myofibroblast function. Our in vitro results showed that oxLDL increased cardiac myofibroblast proliferation, triggered an increase in the synthesis of collagen type I and fibronectin containing extra domain A, and stimulated collagen type I secretion. oxLDL also decreased cardiac myofibroblast migration, collagen gel contraction and cell area, without modifying ?-smooth muscle actin protein levels. These effects were dependent on LOX-1, because LOX-1 knockdown abolished oxLDL effects. Collectively these data showed that oxLDL has important modulatory effects on cardiac myofibroblast function.
  
  Copyright © 2020 Elsevier Inc. All rights reserved.
  
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• A cathelicidin-related antimicrobial peptide suppresses cardiac hypertrophy induced by pressure overload by regulating IGFR1/PI3K/AKT and TLR9/AMPK?.
  Cell Death Dis

  2020 Feb;11(2):96. doi: 10.1038/s41419-020-2296-4.
  
  Wang Xiaofang, Chen Linlin, Zhao Xiaoyan, Xiao Lili, Yi Shanting, Kong Yawei, Jiang Yan, Zhang Jinying,
  
  Abstract
  
  Cathelicidin-related antimicrobial peptide (CRAMP), an antimicrobial peptide, was reported to protect against myocardial ischemia/reperfusion injury. However, the effect of CRAMP on pressure overload-induced cardiac hypertrophy was unknown. This study explored the role of CRAMP on cardiac hypertrophy. A cardiac hypertrophy mouse model was induced by aortic banding surgery. Seven days after surgery, mice were given mCRAMP by intraperitoneal injection (8?mg/kg/d) for 7 weeks. Cardiac hypertrophy was evaluated by the hypertrophic response and fibrosis level as well as cardiac function. Mice were also injected with AAV9-shCRAMP to knockdown CRAMP in the mouse heart. CRAMP levels first increased and then reduced in the remodeling heart, as well as in angiotensin II-stimulated endothelial cells but not in cardiomyocytes and fibroblasts. mCRAMP protected against the pressure overload-induced cardiac remodeling process, while CRAMP knockdown accelerated this process. mCRAMP reduced the inflammatory response and oxidative stress in the hypertrophic heart, while mCRAMP deficiency deteriorated the pressure overload-induced inflammatory response and oxidative stress. mCRAMP inhibited the angiotensin II-stimulated hypertrophic response and oxidative stress in neonatal rat cardiomyocytes, but mCRAMP did not help the angiotensin II-induced inflammatory response and oxidative stress in endothelial cells. Mechanistically, we found that mCRAMP suppressed the cardiac hypertrophic response by activating the IGFR1/PI3K/AKT pathway via directly binding to IGFR1. AKT knockout mice completely reversed the anti-hypertrophic effect of mCRAMP but not its anti-oxidative effect. We also found that mCRAMP ameliorated cardiac oxidative stress by activating the TLR9/AMPKa pathway. This was confirmed by a TLR9 knockout mouse experiment, in which a TLR9 knockout partly reversed the anti-hypertrophic effect of mCRAMP and completely counteracted the anti-oxidative effect of mCRAMP. In summary, mCRAMP protected against pressure overload-induced cardiac hypertrophy by activating both the IGFR1/PI3K/AKT and TLR9/AMPKa pathways in cardiomyocytes.
  
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• Lack of Thy1 defines a pathogenic fraction of cardiac fibroblasts in heart failure.
  Biomaterials

  2020 Apr;236():119824. doi: S0142-9612(20)30070-3.
  
  Li Yanzhen, Song Daniel, Mao Lan, Abraham Dennis M, Bursac Nenad,
  
  Abstract
  
  In response to heart injury, inflammation, or mechanical overload, quiescent cardiac fibroblasts (CFs) can become activated myofibroblasts leading to pathological matrix remodeling and decline in cardiac function. Specific targeting of fibroblasts may thus enable new therapeutic strategies to delay or reverse the progression of heart failure and cardiac fibrosis. However, it remains unknown if all CFs are equally responsive to specific pathological insults and if there exist sub-populations of resident fibroblasts in the heart that have distinctive pathogenic phenotypes. Here, we show that in response to transverse aortic constriction (TAC)-induced heart failure, previously uncharacterized Thy1 (Thy1-/MEFSK4+/CD45-/CD31-) fraction of mouse ventricular fibroblasts became more abundant and attained a more activated, pro-fibrotic myofibroblast phenotype compared to Thy1 fraction. In a tissue-engineered 3D co-culture model of healthy cardiomyocytes and freshly isolated CFs, Thy1 CFs from TAC hearts significantly decreased cardiomyocyte contractile function and calcium transient amplitude, and increased extracellular collagen deposition yielding a profibrotic heart tissue phenotype. In vivo, mice with global knockout of Thy1 developed more severe cardiac dysfunction and fibrosis in response to TAC-induced heart failure than wild-type mice. Taken together, our studies identify cardiac myofibroblasts lacking Thy1 as a pathogenic CF fraction in cardiac fibrosis and suggest important roles of Thy1 in pathophysiology of heart failure.
  
  Copyright © 2020 Elsevier Ltd. All rights reserved.
  
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• The Diabetic Cardiac Fibroblast: Mechanisms Underlying Phenotype and Function.
  Int J Mol Sci

  2020 Feb;21(3):. doi: E970.
  
  Levick Scott P, Widiapradja Alexander,
  
  Abstract
  
  Diabetic cardiomyopathy involves remodeling of the heart in response to diabetes that includes microvascular damage, cardiomyocyte hypertrophy, and cardiac fibrosis. Cardiac fibrosis is a major contributor to diastolic dysfunction that can ultimately result in heart failure with preserved ejection fraction. Cardiac fibroblasts are the final effector cell in the process of cardiac fibrosis. This review article aims to describe the cardiac fibroblast phenotype in response to high-glucose conditions that mimic the diabetic state, as well as to explain the pathways underlying this phenotype. As such, this review focuses on studies conducted on isolated cardiac fibroblasts. We also describe molecules that appear to oppose the pro-fibrotic actions of high glucose on cardiac fibroblasts. This represents a major gap in knowledge in the field that needs to be addressed.
  
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