1 3931 84 LIVER INJURY AND THE ACTIVATION OF THE HEPATIC MYOFIBROBLASTS. LIVER FIBROSIS IS A WOUND HEALING PROCESS, THE END RESULT OF CHRONIC LIVER INJURY ELICITED BY DIFFERENT NOXIOUS STIMULI. ACTIVATED HEPATIC STELLATE CELLS OR MYOFIBROBLASTS AND PORTAL MYOFIBROBLASTS ARE CONSIDERED AS THE MAIN PRODUCERS OF THE EXTRACELLULAR MATRIX IN THE LIVER. UPON LIVER INJURY THE QUIESCENT STELLATE CELLS TRANSDIFFERENTIATE INTO MYOFIBROBLASTS A PROCESS HIGHLIGHTED BY THE LOSS OF VITAMIN A STORES, UPREGULATION OF INTERSTITIAL TYPE COLLAGENS, SMOOTH MUSCLE ALPHA ACTIN, MATRIX METALLOPROTEINASES, PROTEOGLYCANS, AND THE INDUCTION OF CELL SURVIVAL PATHWAYS. ACTIVATION OF HEPATIC STELLATE CELLS IS A RESULT OF A COMPLEX INTERPLAY BETWEEN THE PARENCHYMAL CELLS, IMMUNE CELLS, EXTRACELLULAR MATRIX MECHANICS AND EXTRAHEPATIC MILIEU SUCH AS THE GUT MICROBIOME. IN THIS REVIEW WE WILL FOCUS ON THE PATHOMECHANISM OF STELLATE CELL ACTIVATION FOLLOWING CHRONIC LIVER INJURY; WITH THE AIM OF IDENTIFYING POSSIBLE TREATMENT TARGETS FOR ANTI-FIBROGENIC AGENTS. 2013 2 699 24 BROMODOMAIN PROTEIN 4 IS A KEY MOLECULAR DRIVER OF TGFBETA1-INDUCED HEPATIC STELLATE CELL ACTIVATION. LIVER FIBROSIS IS CHARACTERIZED BY THE EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX IN LIVER. CHRONIC LIVER INJURY INDUCES THE ACTIVATION OF HEPATIC STELLATE CELL (HSCS), A KEY STEP IN LIVER FIBROGENESIS. THE ACTIVATED HSC IS THE PRIMARY SOURCE OF ECM AND CONTRIBUTES SIGNIFICANTLY TO LIVER FIBROSIS. TGFBETA1 IS THE MOST POTENT PRO-FIBROTIC CYTOKINE. BROMODOMAIN PROTEIN 4 (BRD4), AN EPIGENETIC READER OF HISTONE ACETYLATION MARKS, WAS CRUCIAL FOR PROFIBROTIC GENE EXPRESSION IN HSCS. THE PRESENT STUDY AIMED TO INVESTIGATE THE ROLES OF BRD4 IN TGFBETA1-DEPENDENT HSC ACTIVATION AND LIVER FIBROSIS, FOCUSING ON TGFBETA1-INDUCED ALTERATIONS OF THE LEVELS OF THE FIBROTIC-RELATED IMPORTANT PROTEINS IN HSCS BY EMPLOYING THE HETEROZYGOUS TGFBETA1 KNOCKOUT MICE AND BRD4 KNOCKDOWN IN VIVO AND IN VITRO. RESULTS REVEALED THAT BRD4 PROTEIN LEVEL WAS SIGNIFICANTLY UPREGULATED BY TGFBETA1 AND BRD4 KNOCKDOWN REDUCED TGFBETA1-INDUCED HSC ACTIVATION AND LIVER FIBROSIS. BRD4 WAS REQUIRED FOR THE INFLUENCES OF TGFBETA1 ON PDGFBETA RECEPTOR AND ON THE PATHWAYS OF SMAD3, STAT3, AND AKT. BRD4 ALSO MEDIATED TGFBETA1-INDUCED INCREASES IN HISTONE ACETYLTRANSFERASE P300, THE PIVOTAL PRO-INFLAMMATORY NFKB P65, AND TISSUE INHIBITOR OF METALLOPROTEINASE 1 WHEREAS BRD4 REDUCED CASPASE-3 PROTEIN LEVELS IN HSCS DURING LIVER INJURY, INDEPENDENT OF TGFBETA1. FURTHER EXPERIMENTS INDICATED THE INTERACTION BETWEEN TGFBETA1-INDUCED BRD4 AND NFKB P65 IN HSCS AND IN LIVER OF TAA-INDUCED LIVER INJURY. HUMAN CIRRHOTIC LIVERS WERE DEMONSTRATED A PARALLEL INCREASE IN THE PROTEIN LEVELS OF BRD4 AND NFKB P65 IN HSCS. THIS STUDY REVEALED THAT BRD4 WAS A KEY MOLECULAR DRIVER OF TGFBETA1-INDUCED HSC ACTIVATION AND LIVER FIBROSIS. 2023 3 3245 23 HEPATIC STELLATE CELLS AS KEY TARGET IN LIVER FIBROSIS. PROGRESSIVE LIVER FIBROSIS, INDUCED BY CHRONIC VIRAL AND METABOLIC DISORDERS, LEADS TO MORE THAN ONE MILLION DEATHS ANNUALLY VIA DEVELOPMENT OF CIRRHOSIS, ALTHOUGH NO ANTIFIBROTIC THERAPY HAS BEEN APPROVED TO DATE. TRANSDIFFERENTIATION (OR "ACTIVATION") OF HEPATIC STELLATE CELLS IS THE MAJOR CELLULAR SOURCE OF MATRIX PROTEIN-SECRETING MYOFIBROBLASTS, THE MAJOR DRIVER OF LIVER FIBROGENESIS. PARACRINE SIGNALS FROM INJURED EPITHELIAL CELLS, FIBROTIC TISSUE MICROENVIRONMENT, IMMUNE AND SYSTEMIC METABOLIC DYSREGULATION, ENTERIC DYSBIOSIS, AND HEPATITIS VIRAL PRODUCTS CAN DIRECTLY OR INDIRECTLY INDUCE STELLATE CELL ACTIVATION. DYSREGULATED INTRACELLULAR SIGNALING, EPIGENETIC CHANGES, AND CELLULAR STRESS RESPONSE REPRESENT CANDIDATE TARGETS TO DEACTIVATE STELLATE CELLS BY INDUCING REVERSION TO INACTIVATED STATE, CELLULAR SENESCENCE, APOPTOSIS, AND/OR CLEARANCE BY IMMUNE CELLS. CELL TYPE- AND TARGET-SPECIFIC PHARMACOLOGICAL INTERVENTION TO THERAPEUTICALLY INDUCE THE DEACTIVATION WILL ENABLE MORE EFFECTIVE AND LESS TOXIC PRECISION ANTIFIBROTIC THERAPIES. 2017 4 2545 26 EPIGENETICS IN LIVER FIBROSIS: COULD HDACS BE A THERAPEUTIC TARGET? CHRONIC LIVER DISEASES (CLD) REPRESENT A WORLDWIDE HEALTH PROBLEM. WHILE CLDS MAY HAVE DIVERSE ETIOLOGIES, A COMMON PATHOGENIC DENOMINATOR IS THE PRESENCE OF LIVER FIBROSIS. CIRRHOSIS, THE END-STAGE OF CLD, IS CHARACTERIZED BY EXTENSIVE FIBROSIS AND IS MARKEDLY ASSOCIATED WITH THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA. THE MOST IMPORTANT EVENT IN HEPATIC FIBROGENESIS IS THE ACTIVATION OF HEPATIC STELLATE CELLS (HSC) FOLLOWING LIVER INJURY. ACTIVATED HSCS ACQUIRE A MYOFIBROBLAST-LIKE PHENOTYPE BECOMING PROLIFERATIVE, FIBROGENIC, AND CONTRACTILE CELLS. WHILE TRANSIENT ACTIVATION OF HSCS IS PART OF THE PHYSIOLOGICAL MECHANISMS OF TISSUE REPAIR, PROTRACTED ACTIVATION OF A WOUND HEALING REACTION LEADS TO ORGAN FIBROSIS. THE PHENOTYPIC CHANGES OF ACTIVATED HSCS INVOLVE EPIGENETIC MECHANISMS MEDIATED BY NON-CODING RNAS (NCRNA) AS WELL AS BY CHANGES IN DNA METHYLATION AND HISTONE MODIFICATIONS. DURING CLD THESE EPIGENETIC MECHANISMS BECOME DEREGULATED, WITH ALTERATIONS IN THE EXPRESSION AND ACTIVITY OF EPIGENETIC MODULATORS. HERE WE PROVIDE AN OVERVIEW OF THE EPIGENETIC ALTERATIONS INVOLVED IN FIBROGENIC HSCS TRANSDIFFERENTIATION WITH PARTICULAR FOCUS ON HISTONES ACETYLATION CHANGES. WE ALSO DISCUSS RECENT STUDIES SUPPORTING THE PROMISING THERAPEUTIC POTENTIAL OF HISTONE DEACETYLASE INHIBITORS IN LIVER FIBROSIS. 2020 5 4501 25 MORPHOGENS AND HEPATIC STELLATE CELL FATE REGULATION IN CHRONIC LIVER DISEASE. HEPATIC STELLATE CELLS (HSC) ARE THE LIVER MESENCHYMAL CELL TYPE WHICH RESPONDS TO HEPATOCELLULAR DAMAGE AND PARTICIPATES IN WOUND HEALING. ALTHOUGH HSC MYOFIBROBLASTIC TRANS-DIFFERENTIATION (ACTIVATION) IS IMPLICATED IN EXCESSIVE EXTRACELLULAR MATRIX DEPOSITION, MOLECULAR UNDERSTANDING OF THIS PHENOTYPIC SWITCH FROM THE VIEWPOINT OF CELL FATE REGULATION IS LIMITED. RECENT STUDIES DEMONSTRATE THE ROLES OF ANTI-ADIPOGENIC MORPHOGENS (WNT, NECDIN, SHH) IN EPIGENETIC REPRESSION OF THE HSC DIFFERENTIATION GENE PPARGAMMA AS A CAUSAL EVENT IN HSC ACTIVATION. THESE MORPHOGENS HAVE POSITIVE CROSS-INTERACTIONS WHICH CONVERGE TO EPIGENETIC REPRESSION OF PPARGAMMA INVOLVING THE METHYL-CPG BINDING PROTEIN MECP2. HOWEVER, THESE MORPHOGENS EXPRESSED BY ACTIVATED HSC MAY ALSO PARTICIPATE IN CROSS-TALK BETWEEN HSC AND HEPATOBLASTS/HEPATOCYTES TO SUPPORT LIVER REGENERATION, AND THEIR ABERRANT REGULATION MAY CONTRIBUTE TO LIVER TUMORIGENESIS. IMPLICATIONS OF HSC-DERIVED MORPHOGENS IN THESE POSSIBILITIES ARE DISCUSSED. 2012 6 4108 16 MECHANISMS AND DISEASE CONSEQUENCES OF NONALCOHOLIC FATTY LIVER DISEASE. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE LEADING CHRONIC LIVER DISEASE WORLDWIDE. ITS MORE ADVANCED SUBTYPE, NONALCOHOLIC STEATOHEPATITIS (NASH), CONNOTES PROGRESSIVE LIVER INJURY THAT CAN LEAD TO CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. HERE WE PROVIDE AN IN-DEPTH DISCUSSION OF THE UNDERLYING PATHOGENETIC MECHANISMS THAT LEAD TO PROGRESSIVE LIVER INJURY, INCLUDING THE METABOLIC ORIGINS OF NAFLD, THE EFFECT OF NAFLD ON HEPATIC GLUCOSE AND LIPID METABOLISM, BILE ACID TOXICITY, MACROPHAGE DYSFUNCTION, AND HEPATIC STELLATE CELL ACTIVATION, AND CONSIDER THE ROLE OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS THAT PROMOTE FIBROSIS PROGRESSION AND RISK OF HEPATOCELLULAR CARCINOMA IN NASH. 2021 7 6910 21 [TRANSFORMING GROWTH FACTOR-BETA AND RENAL FIBROSIS]. TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA) IS A DRIVING FORCE OF RENAL FIBROSIS, WHICH MAY LEAD TO CHRONIC KIDNEY DISEASES AND EVEN END STAGE RENAL DISEASES. BY ACTIVATING CANONICAL AND NON-CANONICAL SIGNALING PATHWAYS, TGF-BETA PROMOTES THE SYNTHESIS OF EXTRACELLULAR MATRIX WHILE PREVENTING THEIR DEGRADATION. IN THE INJURED KIDNEY, TGF-BETA INDUCES APOPTOSIS, PROLIFERATION AND FIBROTIC RESPONSE OF RENAL CELLS INCLUDING EPITHELIAL CELLS, ENDOTHELIAL CELLS, PODOCYTES, FIBROBLASTS, PERICYTES AND MACROPHAGES, AND IT ALSO PROMOTES TRANSDIFFERENTIATION, ACTIVATION AND PROLIFERATION OF MYOFIBROBLASTS. ADDITIONALLY, TGF-BETA EXERTS PROFIBROTIC EFFECTS BY INTERPLAYING WITH OTHER SIGNALING PATHWAYS LIKE BMP-7, WNT/BETA-CATENIN AND MAP KINASE. SMAD3 IS THE CENTRAL PATHOLOGICAL GENE IN RENAL FIBROSIS, AND EPIGENETIC REGULATION OF TGF-BETA/SMAD3 IS A HOT TOPIC IN KIDNEY FIELD. ALTHOUGH DIRECT TARGETING TGF-BETA MAY CAUSE SIDE EFFECTS INCLUDING TUMORIGENESIS AND IMMUNE DISEASES, THE THERAPEUTIC STRATEGIES TARGETING THE BALANCE OF DOWNSTREAM SMAD3 AND SMAD7 MAY PREVENT OR DELAY THE PROGRESSION OF FIBROTIC KIDNEY DISEASE. 2018 8 2322 23 EPIGENETIC REGULATION OF HEPATIC STELLATE CELL ACTIVATION AND LIVER FIBROSIS. CHRONIC LIVER INJURY TO HEPATOCYTES OR CHOLANGIOCYTES, WHEN LEFT UNMANAGED, LEADS TO THE DEVELOPMENT OF LIVER FIBROSIS, A CONDITION CHARACTERIZED BY THE EXCESSIVE INTRAHEPATIC DEPOSITION OF EXTRACELLULAR MATRIX PROTEINS. ACTIVATED HEPATIC STELLATE CELLS CONSTITUTE THE PREDOMINANT SOURCE OF EXTRACELLULAR MATRIX IN FIBROTIC LIVERS AND THEIR TRANSITION FROM A QUIESCENT STATE DURING FIBROGENESIS IS ASSOCIATED WITH IMPORTANT ALTERATIONS IN THEIR TRANSCRIPTIONAL AND EPIGENETIC LANDSCAPE. AREAS COVERED: WE BRIEFLY DESCRIBE THE PROCESSES INVOLVED IN HEPATIC STELLATE CELL ACTIVATION AND DISCUSS OUR CURRENT UNDERSTANDING OF ALTERATIONS IN THE EPIGENETIC LANDSCAPE, I.E DNA METHYLATION, HISTONE MODIFICATIONS AND THE FUNCTIONAL ROLE OF NON-CODING RNAS THAT ACCOMPANY THIS KEY EVENT IN THE DEVELOPMENT OF CHRONIC LIVER DISEASE. EXPERT COMMENTARY: ALTHOUGH GREAT PROGRESS HAS BEEN MADE, OUR UNDERSTANDING OF THE EPIGENETIC REGULATION OF HEPATIC STELLATE CELL ACTIVATION IS LIMITED AND, THUS FAR, INSUFFICIENT TO ALLOW THE DEVELOPMENT OF EPIGENETIC DRUGS THAT CAN SELECTIVELY INTERRUPT LIVER FIBROSIS. 2016 9 4448 31 MOLECULAR MECHANISM AND TREATMENT OF VIRAL HEPATITIS-RELATED LIVER FIBROSIS. HEPATIC FIBROSIS IS A WOUND-HEALING RESPONSE TO VARIOUS CHRONIC STIMULI, INCLUDING VIRAL HEPATITIS B OR C INFECTION. ACTIVATED MYOFIBROBLASTS, PREDOMINANTLY DERIVED FROM THE HEPATIC STELLATE CELLS (HSCS), REGULATE THE BALANCE BETWEEN MATRIX METALLOPROTEINASES AND THEIR TISSUE INHIBITORS TO MAINTAIN EXTRACELLULAR MATRIX HOMEOSTASIS. TRANSFORMING GROWTH FACTOR-BETA AND PLATELET-DERIVED GROWTH FACTOR ARE CLASSIC PROFIBROGENIC SIGNALS THAT ACTIVATE HSC PROLIFERATION. IN ADDITION, PROINFLAMMATORY CYTOKINES AND CHEMOKINES COORDINATE MACROPHAGES, T CELLS, NK/NKT CELLS, AND LIVER SINUSOIDAL ENDOTHELIAL CELLS IN COMPLEX FIBROGENIC AND REGRESSION PROCESSES. IN ADDITION, FIBROGENESIS INVOLVES ANGIOGENESIS, METABOLIC REPROGRAMMING, AUTOPHAGY, MICRORNA, AND EPIGENETIC REGULATIONS. HEPATIC INFLAMMATION IS THE DRIVING FORCE BEHIND LIVER FIBROSIS; HOWEVER, HOST SINGLE NUCLEOTIDE POLYMORPHISMS AND VIRAL FACTORS, INCLUDING THE GENOTYPE, VIRAL LOAD, VIRAL MUTATION, AND VIRAL PROTEINS, HAVE BEEN ASSOCIATED WITH FIBROSIS PROGRESSION. ELIMINATING THE UNDERLYING ETIOLOGY IS THE MOST CRUCIAL ANTIFIBROTIC THERAPY. GROWING EVIDENCE HAS INDICATED THAT PERSISTENT VIRAL SUPPRESSION WITH ANTIVIRAL THERAPY CAN RESULT IN FIBROSIS REGRESSION, REDUCED LIVER DISEASE PROGRESSION, DECREASED HEPATOCELLULAR CARCINOMA, AND IMPROVED CHANCES OF SURVIVAL. PRECLINICAL STUDIES AND CLINICAL TRIALS ARE CURRENTLY EXAMINING SEVERAL INVESTIGATIONAL AGENTS THAT TARGET KEY FIBROGENIC PATHWAYS; THE RESULTS ARE PROMISING AND SHED LIGHT ON THIS DEBILITATING ILLNESS. 2014 10 2817 23 FIBROSIS IN THE LIVER: ACUTE PROTECTION AND CHRONIC DISEASE. THE UNDERSTANDING OF THE CELLULAR AND MOLECULAR MECHANISMS OF THE FIBROTIC WOUND-HEALING RESPONSE OF THE LIVER HAS MADE DRAMATIC PROGRESS IN THE PAST 20 YEARS. HEPATIC STELLATE CELLS (HSCS), WHICH AFTER LIVER INJURY PROLIFERATE AND TRANSDIFFERENTIATE TO MYOFIBROBLASTS, HAVE EMERGED AS THE PRIMARY SOURCE OF THE FIBROTIC RESPONSE, EVEN THOUGH OTHER FIBROGENIC CELLS MAY ALSO CONTRIBUTE TO THE PRODUCTION OF EXTRACELLULAR MATRIX (ECM). ADVANCES IN THE UNDERSTANDING OF HSC REGULATION INCLUDE APOPTOTIC SIGNALING, ANGIOGENIC SIGNALING, AND RESPONSES TO OXIDATIVE STRESS. THE ECM HAS EMERGED NOT ONLY AS A STRUCTURAL SCAFFOLD, BUT ALSO AS A DYNAMIC AND INTERACTIVE MATRIX REGULATING STELLATE CELL ACTIVATION. ADDITIONALLY, THE INNATE IMMUNE SYSTEM AND IMMUNE SIGNALING, AS WELL AS A BROADENING UNDERSTANDING OF THE TRANSCRIPTIONAL REGULATION INCLUDING MICRORNAS AND EPIGENETIC EVENTS OFFER POTENTIAL THERAPEUTIC TARGETS. UNRAVELING GENETIC DETERMINANTS RELATED TO MECHANISMS OF HEPATIC FIBROGENESIS PROMISE INDIVIDUALIZED THERAPY OR PREVENTION. HEPATIC FIBROSIS AND CIRRHOSIS HAVE EMERGED AS TREATABLE AND POTENTIALLY REVERSIBLE CONSEQUENCE OF CHRONIC LIVER DISEASE. 2010 11 2502 26 EPIGENETICS AND LIVER FIBROSIS. LIVER FIBROSIS ARISES BECAUSE PROLONGED INJURY COMBINED WITH EXCESSIVE SCAR DEPOSITION WITHIN HEPATIC PARENCHYMA ARISING FROM OVERACTIVE WOUND HEALING RESPONSE MEDIATED BY ACTIVATED MYOFIBROBLASTS. FIBROSIS IS THE COMMON END POINT FOR ANY TYPE OF CHRONIC LIVER INJURY INCLUDING ALCOHOLIC LIVER DISEASE, NONALCOHOLIC FATTY LIVER DISEASE, VIRAL HEPATITIS, AND CHOLESTATIC LIVER DISEASES. ALTHOUGH GENETIC INFLUENCES ARE IMPORTANT, IT IS EPIGENETIC MECHANISMS THAT HAVE BEEN SHOWN TO ORCHESTRATE MANY ASPECTS OF FIBROGENESIS IN THE LIVER. NEW DISCOVERIES IN THE FIELD ARE LEADING TOWARD THE DEVELOPMENT OF EPIGENETIC BIOMARKERS AND TARGETED THERAPIES. THIS REVIEW CONSIDERS EPIGENETIC MECHANISMS AS WELL AS RECENT ADVANCES IN EPIGENETIC PROGRAMMING IN THE CONTEXT OF HEPATIC FIBROSIS. 2017 12 4132 25 MECHANISMS OF HEPATIC FIBROGENESIS. SUBSTANTIAL IMPROVEMENTS IN THE TREATMENT OF CHRONIC LIVER DISEASE HAVE ACCELERATED INTEREST IN UNCOVERING THE MECHANISMS UNDERLYING HEPATIC FIBROSIS AND ITS RESOLUTION. ACTIVATION OF RESIDENT HEPATIC STELLATE CELLS INTO PROLIFERATIVE, CONTRACTILE, AND FIBROGENIC CELLS IN LIVER INJURY REMAINS A DOMINANT THEME DRIVING THE FIELD. HOWEVER, SEVERAL NEW AREAS OF RAPID PROGRESS IN THE PAST 5-10 YEARS ALSO HAVE TAKEN ROOT, INCLUDING: (1) IDENTIFICATION OF DIFFERENT FIBROGENIC POPULATIONS APART FROM RESIDENT STELLATE CELLS, FOR EXAMPLE, PORTAL FIBROBLASTS, FIBROCYTES, AND BONE-MARROW-DERIVED CELLS, AS WELL AS CELLS DERIVED FROM EPITHELIAL MESENCHYMAL TRANSITION; (2) EMERGENCE OF STELLATE CELLS AS FINELY REGULATED DETERMINANTS OF HEPATIC INFLAMMATION AND IMMUNITY; (3) ELUCIDATION OF MULTIPLE PATHWAYS CONTROLLING GENE EXPRESSION DURING STELLATE CELL ACTIVATION INCLUDING TRANSCRIPTIONAL, POST-TRANSCRIPTIONAL, AND EPIGENETIC MECHANISMS; (4) RECOGNITION OF DISEASE-SPECIFIC PATHWAYS OF FIBROGENESIS; (5) RE-EMERGENCE OF HEPATIC MACROPHAGES AS DETERMINANTS OF MATRIX DEGRADATION IN FIBROSIS RESOLUTION AND THE IMPORTANCE OF MATRIX CROSS-LINKING AND SCAR MATURATION IN DETERMINING REVERSIBILITY; AND (6) HINTS THAT HEPATIC STELLATE CELLS MAY CONTRIBUTE TO HEPATIC STEM CELL BEHAVIOR, CANCER, AND REGENERATION. CLINICAL AND TRANSLATIONAL IMPLICATIONS OF THESE ADVANCES HAVE BECOME CLEAR, AND HAVE BEGUN TO IMPACT SIGNIFICANTLY ON THE MANAGEMENT AND OUTLOOK OF PATIENTS WITH CHRONIC LIVER DISEASE. 2008 13 4976 30 PATHOPHYSIOLOGICAL MECHANISMS OF HEPATIC STELLATE CELLS ACTIVATION IN LIVER FIBROSIS. LIVER FIBROSIS IS A COMPLEX PATHOLOGICAL PROCESS CONTROLLED BY A VARIETY OF CELLS, MEDIATORS AND SIGNALING PATHWAYS. HEPATIC STELLATE CELLS PLAY A CENTRAL ROLE IN THE DEVELOPMENT OF LIVER FIBROSIS. IN CHRONIC LIVER DISEASE, HEPATIC STELLATE CELLS UNDERGO DRAMATIC PHENOTYPIC ACTIVATION AND ACQUIRE FIBROGENIC PROPERTIES. THIS REVIEW FOCUSES ON THE PATHOPHYSIOLOGICAL MECHANISMS OF HEPATIC STELLATE CELLS ACTIVATION IN LIVER FIBROSIS. THEY ENTER THE CELL CYCLE UNDER THE INFLUENCE OF VARIOUS TRIGGERS. THE "INITIATION" PHASE OF HEPATIC STELLATE CELLS ACTIVATION OVERLAPS AND CONTINUES WITH THE "PERPETUATION" PHASE, WHICH IS CHARACTERIZED BY A PRONOUNCED INFLAMMATORY AND FIBROGENIC REACTION. THIS IS FOLLOWED BY A RESOLUTION PHASE IF THE INJURY SUBSIDES. KNOWLEDGE OF THESE PATHOPHYSIOLOGICAL MECHANISMS PAVED THE WAY FOR DRUGS AIMED AT PREVENTING THE DEVELOPMENT AND PROGRESSION OF LIVER FIBROSIS. IN THIS RESPECT, IMPAIRMENTS IN INTRACELLULAR SIGNALING, EPIGENETIC CHANGES AND CELLULAR STRESS RESPONSE CAN BE THE TARGETS OF THERAPY WHERE THE GOAL IS TO DEACTIVATE HEPATIC STELLATE CELLS. POTENTIAL ANTIFIBROTIC THERAPY MAY FOCUS ON INDUCING HEPATIC STELLATE CELLS TO RETURN TO AN INACTIVE STATE THROUGH CELLULAR AGING, APOPTOSIS, AND/OR CLEARANCE BY IMMUNE CELLS, AND SERVE AS POTENTIAL ANTIFIBROTIC THERAPY. IT IS ESPECIALLY IMPORTANT TO PREVENT THE FORMATION OF LIVER CIRRHOSIS SINCE THE ONLY RADICAL APPROACH TO ITS TREATMENT IS LIVER TRANSPLANTATION WHICH CAN BE PERFORMED IN ONLY A LIMITED NUMBER OF COUNTRIES. 2022 14 6372 21 THE ROLE OF MIR-29A IN THE REGULATION, FUNCTION, AND SIGNALING OF LIVER FIBROSIS. BOTH FIBROSIS AND CIRRHOSIS OF THE LIVER ARE THE END RESULTS OF MOST KINDS OF CHRONIC LIVER DAMAGE AND REPRESENT A COMMON BUT DIFFICULT CLINICAL CHALLENGE THROUGHOUT THE WORLD. THE INHIBITION OF THE FIBROGENIC, PROLIFERATIVE, AND MIGRATORY EFFECTS OF HEPATIC STELLATE CELLS (HSCS) HAS BECOME AN EXPERIMENTAL THERAPY FOR PREVENTING AND EVEN REVERSING HEPATIC FIBROSIS. FURTHERMORE, A COMPLETE UNDERSTANDING OF THE FUNCTION OF NON-CODING RNA-MEDIATED EPIGENETIC MECHANISMS IN HSC ACTIVATION MAY IMPROVE OUR PERCEPTION OF LIVER FIBROSIS PATHOGENESIS. THIS REVIEW FOCUSES ON THE EVOLVING VIEW OF THE MOLECULAR MECHANISMS BY WHICH HSC ACTIVATION BY MIR-29A SIGNALING MAY MODERATE THE PROFIBROGENIC PHENOTYPE OF THESE CELLS, THUS SUPPORTING THE USE OF MIR-29A AGONISTS AS A POTENTIAL THERAPY FOR TREATING LIVER FIBROSIS IN THE FUTURE. 2018 15 3512 25 IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS IS A DEVASTATING, AGE-RELATED LUNG DISEASE OF UNKNOWN CAUSE THAT HAS FEW TREATMENT OPTIONS. THIS DISEASE WAS ONCE THOUGHT TO BE A CHRONIC INFLAMMATORY PROCESS, BUT CURRENT EVIDENCE INDICATES THAT THE FIBROTIC RESPONSE IS DRIVEN BY ABNORMALLY ACTIVATED ALVEOLAR EPITHELIAL CELLS (AECS). THESE CELLS PRODUCE MEDIATORS THAT INDUCE THE FORMATION OF FIBROBLAST AND MYOFIBROBLAST FOCI THROUGH THE PROLIFERATION OF RESIDENT MESENCHYMAL CELLS, ATTRACTION OF CIRCULATING FIBROCYTES, AND STIMULATION OF THE EPITHELIAL TO MESENCHYMAL TRANSITION. THE FIBROBLAST AND MYOFIBROBLAST FOCI SECRETE EXCESSIVE AMOUNTS OF EXTRACELLULAR MATRIX, MAINLY COLLAGENS, RESULTING IN SCARRING AND DESTRUCTION OF THE LUNG ARCHITECTURE. THE MECHANISMS THAT LINK IDIOPATHIC PULMONARY FIBROSIS WITH AGEING AND ABERRANT EPITHELIAL ACTIVATION ARE UNKNOWN; EVIDENCE SUGGESTS THAT THE ABNORMAL RECAPITULATION OF DEVELOPMENTAL PATHWAYS AND EPIGENETIC CHANGES HAVE A ROLE. IN THIS SEMINAR, WE REVIEW RECENT DATA ON THE CLINICAL COURSE, THERAPEUTIC OPTIONS, AND UNDERLYING MECHANISMS THOUGHT TO BE INVOLVED IN THE PATHOGENESIS OF IDIOPATHIC PULMONARY FIBROSIS. 2011 16 1348 27 DETERMINANTS OF FIBROSIS PROGRESSION AND REGRESSION IN NASH. CIRRHOSIS HAS BECOME THE MAJOR LIVER-RELATED CLINICAL ENDPOINT IN NON-ALCOHOLIC STEATOHEPATITIS (NASH). HOWEVER, PROGRESSION TO CIRRHOSIS IS LESS PREDICTABLE IN NASH THAN IN OTHER CHRONIC LIVER DISEASES. THIS IS DUE TO THE COMPLEX AND MULTIFACTORIAL AETIOLOGY OF NASH, WHICH IS DETERMINED BY LIFESTYLE AND NUTRITION, MULTIPLE GENETIC AND EPIGENETIC FACTORS, AND A PROMINENT ROLE OF HEPATIC AND EXTRAHEPATIC COMORBIDITIES. THUS, MODEST CHANGES IN THESE COFACTORS CAN ALSO INDUCE FIBROSIS REGRESSION, AT LEAST IN PATIENTS WITH PRECIRRHOTIC LIVER DISEASE. FIBROGENESIS IN NASH CORRELATES WITH, BUT IS INDIRECTLY COUPLED TO, CLASSICAL INFLAMMATION, SINCE FIBROSIS PROGRESSION IS DRIVEN BY REPETITIVE PERIODS OF REPAIR. WHILE HEPATOCYTE LIPOAPOPTOSIS IS A KEY DRIVING FORCE OF FIBROSIS PROGRESSION, ACTIVATED HEPATIC STELLATE CELLS, MYOFIBROBLASTS, CHOLANGIOCYTES, MACROPHAGES AND COMPONENTS OF THE PATHOLOGICAL EXTRACELLULAR MATRIX ARE MAJOR FIBROGENIC EFFECTORS AND THUS PHARMACOLOGICAL TARGETS FOR THERAPIES AIMED AT INHIBITION OF FIBROSIS PROGRESSION OR INDUCTION OF FIBROSIS REVERSAL. THE ADVENT OF NOVEL, HIGHLY SENSITIVE AND SPECIFIC SERUM BIOMARKERS AND IMAGING METHODS TO ASSESS THE DYNAMICS OF LIVER FIBROSIS IN NASH WILL IMPROVE DETECTION, STRATIFICATION AND FOLLOW-UP OF PATIENTS WITH PROGRESSIVE NASH . THESE NON-INVASIVE TOOLS WILL ALSO PROMOTE THE CLINICAL DEVELOPMENT OF ANTIFIBROTIC DRUGS, BY PERMITTING THE DESIGN OF LEAN PROOF-OF-CONCEPT STUDIES, AND ENABLING DEVELOPMENT OF A PERSONALISED ANTIFIBROTIC THERAPY FOR PATIENTS WITH RAPID FIBROSIS PROGRESSION OR ADVANCED DISEASE. 2018 17 1764 23 EARLY-IMMEDIATE GENE EGR1 IS ASSOCIATED WITH TGFBETA1 REGULATION OF EPIGENETIC READER BROMODOMAIN-CONTAINING PROTEIN 4 VIA THE CANONICAL SMAD3 SIGNALING IN HEPATIC STELLATE CELLS IN VITRO AND IN VIVO. UPON CHRONIC DAMAGE TO THE LIVER, MULTIPLE CYTOKINES STIMULATE HEPATIC STELLATE CELLS (HSCS), CAUSING THE ALTERATIONS OF GENE EXPRESSION PROFILES AND THUS LEADING TO HSC ACTIVATION, A KEY STEP IN LIVER FIBROGENESIS. ACTIVATED HSCS ARE THE DOMINANT CONTRIBUTORS TO LIVER FIBROSIS. BROMODOMAIN CONTAINING PROTEIN 4 (BRD4), AN IMPORTANT EPIGENETIC READER, WAS DEMONSTRATED TO CONCENTRATE ON HUNDREDS OF ENHANCERS ASSOCIATED WITH GENES INVOLVED IN MULTIPLE PROFIBROTIC PATHWAYS, THEREBY DIRECTING HSC ACTIVATION AND THE FIBROTIC RESPONSES. THE PRESENT STUDIES WERE DESIGNED TO EXAMINE THE EFFECT OF TRANSFORMING GROWTH FACTOR BETA-1 (TGFBETA1), THE MOST POTENT PRO-FIBROTIC CYTOKINE, ON BRD4 EXPRESSION IN HSCS AND, IF SO, ELUCIDATED THE UNDERLYING MECHANISMS IN VITRO AND IN VIVO. THE EXPERIMENTS EMPLOYED THE HETEROGENEOUS TGFBETA1 KNOCKOUT (TGFBETA1(+/-) ) MICE, GENE KNOCKDOWN IN VIVO, AND A MODEL OF THIOACETAMIDE (TAA)-INDUCED LIVER INJURY. THE RESULTS REVEALED THAT TGFBETA1 ENHANCED BRD4 EXPRESSION IN HSCS, WHICH WAS MEDIATED, AT LEAST, BY SMAD3 SIGNALING AND EARLY-IMMEDIATE GENE EGR1 (EARLY GROWTH RESPONSE-1). TGFBETA1-INDUCED SMAD3 SIGNALING INCREASED EGR1 EXPRESSION AND PROMOTED EGR1 BINDING TO BRD4 PROMOTER AT A SITE AROUND -111 BP, PROMOTING BRD4 EXPRESSION. EGR1 KNOCKDOWN REDUCED BRD4 EXPRESSION IN HSCS IN A MOUSE MODEL OF TAA-INDUCED LIVER INJURY AND LESSENED LIVER FIBROSIS. DOUBLE FLUORESCENCE STAINING DEMONSTRATED A STRONG INCREASE IN BRD4 EXPRESSION IN ACTIVATED HSCS IN FIBROTIC AREAS OF THE HUMAN LIVERS, PARALLELING THE UPREGULATION OF P-SMAD3 AND EGR1. THIS RESEARCH SUGGESTED NOVEL MOLECULAR EVENTS UNDERLYING THE ROLES OF THE MASTER PRO-FIBROTIC CYTOKINE TGFBETA1 IN HSC ACTIVATION AND LIVER FIBROGENESIS. 2022 18 5992 25 TGF-BETA: THE MASTER REGULATOR OF FIBROSIS. TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA) IS THE PRIMARY FACTOR THAT DRIVES FIBROSIS IN MOST, IF NOT ALL, FORMS OF CHRONIC KIDNEY DISEASE (CKD). INHIBITION OF THE TGF-BETA ISOFORM, TGF-BETA1, OR ITS DOWNSTREAM SIGNALLING PATHWAYS SUBSTANTIALLY LIMITS RENAL FIBROSIS IN A WIDE RANGE OF DISEASE MODELS WHEREAS OVEREXPRESSION OF TGF-BETA1 INDUCES RENAL FIBROSIS. TGF-BETA1 CAN INDUCE RENAL FIBROSIS VIA ACTIVATION OF BOTH CANONICAL (SMAD-BASED) AND NON-CANONICAL (NON-SMAD-BASED) SIGNALLING PATHWAYS, WHICH RESULT IN ACTIVATION OF MYOFIBROBLASTS, EXCESSIVE PRODUCTION OF EXTRACELLULAR MATRIX (ECM) AND INHIBITION OF ECM DEGRADATION. THE ROLE OF SMAD PROTEINS IN THE REGULATION OF FIBROSIS IS COMPLEX, WITH COMPETING PROFIBROTIC AND ANTIFIBROTIC ACTIONS (INCLUDING IN THE REGULATION OF MESENCHYMAL TRANSITIONING), AND WITH COMPLEX INTERPLAY BETWEEN TGF-BETA/SMADS AND OTHER SIGNALLING PATHWAYS. STUDIES OVER THE PAST 5 YEARS HAVE IDENTIFIED ADDITIONAL MECHANISMS THAT REGULATE THE ACTION OF TGF-BETA1/SMAD SIGNALLING IN FIBROSIS, INCLUDING SHORT AND LONG NONCODING RNA MOLECULES AND EPIGENETIC MODIFICATIONS OF DNA AND HISTONE PROTEINS. ALTHOUGH DIRECT TARGETING OF TGF-BETA1 IS UNLIKELY TO YIELD A VIABLE ANTIFIBROTIC THERAPY DUE TO THE INVOLVEMENT OF TGF-BETA1 IN OTHER PROCESSES, GREATER UNDERSTANDING OF THE VARIOUS PATHWAYS BY WHICH TGF-BETA1 CONTROLS FIBROSIS HAS IDENTIFIED ALTERNATIVE TARGETS FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS TO HALT THIS MOST DAMAGING PROCESS IN CKD. 2016 19 2164 27 EPIGENETIC MECHANISMS IN HEPATIC STELLATE CELL ACTIVATION DURING LIVER FIBROSIS AND CARCINOGENESIS. LIVER FIBROSIS IS AN ESSENTIAL COMPONENT OF CHRONIC LIVER DISEASE (CLD) AND HEPATOCARCINOGENESIS. THE FIBROTIC STROMA IS A CONSEQUENCE OF SUSTAINED LIVER DAMAGE COMBINED WITH EXACERBATED EXTRACELLULAR MATRIX (ECM) ACCUMULATION. IN THIS CONTEXT, ACTIVATION OF HEPATIC STELLATE CELLS (HSCS) PLAYS A KEY ROLE IN BOTH INITIATION AND PERPETUATION OF FIBROGENESIS. THESE CELLS SUFFER PROFOUND REMODELING OF GENE EXPRESSION IN THIS PROCESS. THIS REVIEW IS FOCUSED ON THE EPIGENETIC ALTERATIONS PARTICIPATING IN THE TRANSDIFFERENTIATION OF HSCS FROM THE QUIESCENT TO ACTIVATED STATE. RECENT ADVANCES IN THE FIELD OF DNA METHYLATION AND POST-TRANSLATIONAL MODIFICATIONS (PTM) OF HISTONES (ACETYLATION AND METHYLATION) PATTERNS ARE DISCUSSED HERE, TOGETHER WITH ALTERED EXPRESSION AND ACTIVITY OF EPIGENETIC REMODELERS. WE ALSO CONSIDER RECENT ADVANCES IN TRANSLATIONAL APPROACHES, INCLUDING THE USE OF EPIGENETIC MARKS AS BIOMARKERS AND THE PROMISING ANTIFIBROTIC PROPERTIES OF EPIGENETIC DRUGS THAT ARE CURRENTLY BEING USED IN PATIENTS. 2019 20 5733 24 SMALL MOLECULES AGAINST THE ORIGIN AND ACTIVATION OF MYOFIBROBLAST FOR RENAL INTERSTITIAL FIBROSIS THERAPY. RENAL INTERSTITIAL FIBROSIS (RIF) IS A COMMON PATHOLOGICAL RESPONSE IN A BROAD RANGE OF PREVALENT CHRONIC KIDNEY DISEASES AND ULTIMATELY LEADS TO RENAL FAILURE AND DEATH. ALTHOUGH RIF CAUSES A HIGH MORBI-MORTALITY WORLDWIDE, EFFECTIVE THERAPEUTIC DRUGS ARE URGENTLY NEEDED. MYOFIBROBLASTS ARE IDENTIFIED AS THE MAIN EFFECTOR DURING THE PROCESS OF RIF. MULTIPLE TYPES OF CELLS, INCLUDING FIBROBLASTS, EPITHELIAL CELLS, ENDOTHELIAL CELLS, MACROPHAGES AND PERICYTES, CONTRIBUTE TO RENAL MYOFIBROBLASTS ORIGIN, AND LOTS OF MEDIATORS, INCLUDING SIGNALING PATHWAYS (TRANSFORMING GROWTH FACTOR-BETA1, MAMMALIAN TARGET OF RAPAMYCIN AND REACTIVE OXYGEN SPECIES) AND EPIGENETIC MODIFICATIONS (HISTONE ACETYLATION, MICRORNA AND LONG NON-CODING RNA) ARE PARTICIPATED IN RENAL MYOFIBROBLASTS ACTIVATION DURING RENAL FIBROGENESIS, SUGGESTING THAT THESE MEDIATORS MAY BE THE PROMISING TARGETS FOR TREATING RIF. IN ADDITION, MANY SMALL MOLECULES SHOW PROFOUND THERAPEUTIC EFFECTS ON RIF BY SUPPRESSING THE ORIGIN AND ACTIVATION OF RENAL MYOFIBROBLASTS. TAKEN TOGETHER, THE REVIEW FOCUSES ON THE MECHANISMS OF THE ORIGIN AND ACTIVATION OF RENAL MYOFIBROBLASTS IN RIF AND THE SMALL MOLECULES AGAINST THEM IMPROVING RIF, WHICH WILL PROVIDE A NEW INSIGHT FOR RIF THERAPY. 2021