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 4199 22 METABOLIC REPROGRAMMING AND CELL FATE REGULATION IN ALCOHOLIC LIVER DISEASE. ALCOHOLIC LIVER DISEASE (ALD) SHOULD BE DEFINED AS A LIFE-STYLE METABOLIC DISEASE. ITS PATHOGENESIS IS DRIVEN BY ALTERED CELL FATE OF BOTH PARENCHYMAL AND NON-PARENCHYMAL LIVER CELL TYPES, CONTRIBUTING TO DIFFERENT PATHOLOGIC SPECTRA. A CRITICAL TURNING POINT IN PROGRESSION OF ALD IS CHRONIC ALCOHOLIC STEATOHEPATITIS (ASH) OR ALCOHOLIC NEUTROPHILIC HEPATITIS (AH), WHICH MARKEDLY PREDISPOSES PATIENTS TO MOST DEVASTATING ALD SEQUELA, CIRRHOSIS AND LIVER CANCER. RESULTS: OUR RESEARCH IDENTIFIES THE PIVOTAL ROLES OF UNIQUE METABOLIC REPROGRAMMING IN M1 ACTIVATION OF HEPATIC MACROPHAGES (HM) AND MYOFIBROBLASTIC ACTIVATION (MF) OF HEPATIC STELLATE CELLS (HSC) IN THE GENESIS OF INFLAMMATION AND FIBROSIS, THE TWO KEY HISTOLOGICAL FEATURES OF CHRONIC ASH AND NEUTROPHILIC AH. FOR M1 HM ACTIVATION, HEIGHTENED PROINFLAMMATORY IRON REDOX SIGNALING IN ENDOSOMES OR CAVEOSOMES RESULTS FROM ALTERED IRON METABOLISM AND STORAGE, PROMOTING IKK/NF-KB ACTIVATION VIA INTERACTIVE ACTIVATION OF P21RAS, TAK1, AND PI3K. FOR MF CELL FATE REGULATION OF HSC, ACTIVATION OF THE MORPHOGEN WNT PATHWAY CAUSED BY THE NUCLEAR PROTEIN NECDIN OR THE SINGLE-PASS TRANS-MEMBRANE PROTEIN DLK1, REPROGRAMS LIPID METABOLISM VIA MECP2-MEDIATED EPIGENETIC REPRESSION OF THE KEY HSC QUIESCENCE GENE PPAR-GAMMA. CONCLUSIONS: THE FINDINGS FROM THESE STUDIES RE-ENFORCE THE IMPORTANCE OF METABOLIC REPROGRAMMING IN CELL FATE REGULATION REQUIRED FOR THE PATHOGENESIS OF ALD. 2015 3 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 4 4436 17 MOLECULAR EVOLUTION OF CHRONIC MYELOID LEUKAEMIA. CHRONIC MYELOID LEUKAEMIA (CML) IS A CLONAL DISORDER OF THE PLURIPOTENT HAEMATOPOIETIC STEM CELL. THE TYPICAL TRIPHASIC COURSE OF CML STARTS WITH THE PREMALIGNANT CHRONIC PHASE INITIATED BY BCR-ABL HYBRID ONCOGENE FORMATION. SECONDARY GENETIC AND EPIGENETIC ABERRATIONS ACCOMPANY THE PROGRESSION TO THE ACCELERATED PHASE AND FATAL BLASTIC CRISIS. PROPERLY TIMED BONE MARROW TRANSPLANTATION IN ELIGIBLE PATIENTS CAN RESULT IN DURABLE REMISSIONS OR CURE. BOTH OF THESE STATES ARE OFTEN ACCOMPANIED BY A LONG-TERM PERSISTENCE OF QUIESCENT LEUKAEMIC CELLS. ACCORDINGLY, A "FUNCTIONAL CURE" (I.E. TUMOUR DORMANCY INDUCTION), RATHER THAN COMPLETE ERADICATION OF THE MALIGNANT CELLS, IS AN ADEQUATE THERAPEUTICAL GOAL. THE LEVEL OF THE RESIDUAL BCR-ABL-POSITIVE CLONES SHOULD BE MONITORED AND SALVAGE TREATMENT INITIATED WHENEVER THESE QUIESCENT LEUKAEMIC CELLS EXIT THEIR DORMANT STATE. 2001 5 5212 18 PRESERVATION OF QUIESCENT CHRONIC MYELOGENOUS LEUKEMIA STEM CELLS BY THE BONE MARROW MICROENVIRONMENT. THE MAJORITY OF LEUKEMIA PATIENTS ACHIEVING REMISSION ULTIMATELY RELAPSE. PERSISTENCE OF LEUKEMIA STEM CELLS (LSC) CAPABLE OF REGENERATING LEUKEMIA IS A MAJOR CAUSE OF RELAPSE. THERE IS A PRESSING NEED TO BETTER UNDERSTAND MECHANISMS OF LSC REGULATION AND THEIR RESISTANCE TO THERAPY IN ORDER TO IMPROVE OUTCOMES FOR LEUKEMIA. CHRONIC MYELOGENOUS LEUKEMIA (CML) IS A LETHAL MYELOPROLIFERATIVE DISORDER THAT THAT IS CAUSED BY HEMATOPOIETIC STEM CELL (HSC) TRANSFORMATION BY THE BCR-ABL TYROSINE KINASE. TREATMENT WITH TYROSINE KINASE INHIBITORS (TKI) HAS REVOLUTIONIZED CML TREATMENT, BUT FAILS TO ELIMINATE LSC RESPONSIBLE FOR PROPAGATING AND REGENERATING LEUKEMIA. THEREFORE, PATIENTS REQUIRE CONTINUED TREATMENT TO PREVENT RELAPSE. LEUKEMIC AND NORMAL STEM CELLS SHARE PROPERTIES OF QUIESCENCE AND SELF-RENEWAL, THAT ARE SUPPORTED BY BONE MARROW NICHES. PERSISTENCE OF LSC AFTER TKI TREATMENT IS RELATED TO TYROSINE KINASE INDEPENDENT MECHANISMS WHICH INCLUDE INTRINSIC PROPERTIES OF LSCS DETERMINED BY EPIGENETIC ALTERATIONS, ALTERED TRANSCRIPTIONAL REGULATORY NETWORKS OR MITOCHONDRIAL/METABOLIC CHANGES. IN ADDITION TO CELL INTRINSIC CHANGES, SIGNALS FROM THE BONE MARROW MICROENVIRONMENT (BMM) PLAY A CRITICAL ROLE IN PROTECTING LSC FROM TKI TREATMENT. EACH TYPE OF ALTERATION MAY OFFER POTENTIAL POINTS OF INTERVENTION FOR THERAPEUTIC TARGETING OF LSC. 2018 6 791 19 CELLULAR AND MOLECULAR NETWORKS IN CHRONIC MYELOID LEUKEMIA: THE LEUKEMIC STEM, PROGENITOR AND STROMAL CELL INTERPLAY. THE USE OF IMATINIB, SECOND AND THIRD GENERATION ABL TYROSINE KINASE INHIBITORS (TKI) (I.E. DASATINIB, NILOTINIB, BOSUTINIB AND PONATINIB) MADE CML A CLINICALLY MANAGEABLE AND, IN A SMALL PERCENTAGE OF CASES, A CURED DISEASE. TKI THERAPY ALSO TURNED CML BLASTIC TRANSFORMATION INTO A RARE EVENT; HOWEVER, DISEASE PROGRESSION STILL OCCURS IN THOSE PATIENTS WHO ARE REFRACTORY, NOT COMPLIANT WITH TKI THERAPY OR DEVELOP RESISTANCE TO MULTIPLE TKIS. IN THE PAST FEW YEARS, IT BECAME CLEAR THAT THE BCRABL1 ONCOGENE DOES NOT OPERATE ALONE TO DRIVE DISEASE EMERGENCE, MAINTENANCE AND PROGRESSION. INDEED, IT SEEMS THAT BONE MARROW (BM) MICROENVIRONMENT-GENERATED SIGNALS AND CELL AUTONOMOUS BCRABL1 KINASE-INDEPENDENT GENETIC AND EPIGENETIC ALTERATIONS ALL CONTRIBUTE TO: I. PERSISTENCE OF A QUIESCENT LEUKEMIC STEM CELL (LSC) RESERVOIR, II. INNATE OR ACQUIRED RESISTANCE TO TKIS, AND III. PROGRESSION INTO THE FATAL BLAST CRISIS STAGE. HEREIN, WE REVIEW THE INTRICATE LEUKEMIC NETWORK IN WHICH ABERRANT, BUT FINELY TUNED, SURVIVAL, MITOGENIC AND SELF-RENEWAL SIGNALS ARE GENERATED BY LEUKEMIC PROGENITORS, STROMAL CELLS, IMMUNE CELLS AND METABOLIC MICROENVIRONMENTAL CONDITIONS (E.G. HYPOXIA) TO PROMOTE LSC MAINTENANCE AND BLASTIC TRANSFORMATION. 2017 7 3702 25 INFLAMMATORY SIGNALING PATHWAYS IN PRELEUKEMIC AND LEUKEMIC STEM CELLS. HEMATOPOIETIC STEM CELLS (HSCS) ARE A RARE SUBSET OF BONE MARROW CELLS THAT USUALLY EXIST IN A QUIESCENT STATE, ONLY ENTERING THE CELL CYCLE TO REPLENISH THE BLOOD COMPARTMENT, THEREBY LIMITING THE POTENTIAL FOR ERRORS IN REPLICATION. INFLAMMATORY SIGNALS THAT ARE RELEASED IN RESPONSE TO ENVIRONMENTAL STRESSORS, SUCH AS INFECTION, TRIGGER ACTIVE CYCLING OF HSCS. THESE INFLAMMATORY SIGNALS CAN ALSO DIRECTLY INDUCE HSCS TO RELEASE CYTOKINES INTO THE BONE MARROW ENVIRONMENT, PROMOTING MYELOID DIFFERENTIATION. AFTER STRESS MYELOPOIESIS IS TRIGGERED, HSCS REQUIRE INTRACELLULAR SIGNALING PROGRAMS TO DEACTIVATE THIS RESPONSE AND RETURN TO STEADY STATE. PROLONGED OR EXCESSIVE EXPOSURE TO INFLAMMATORY CYTOKINES, SUCH AS IN PROLONGED INFECTION OR IN CHRONIC RHEUMATOLOGIC CONDITIONS, CAN LEAD TO CONTINUED HSC CYCLING AND EVENTUAL HSC LOSS. THIS PROMOTES BONE MARROW FAILURE, AND CAN PRECIPITATE PRELEUKEMIC STATES OR LEUKEMIA THROUGH THE ACQUISITION OF GENETIC AND EPIGENETIC CHANGES IN HSCS. THIS CAN OCCUR THROUGH THE INITIATION OF CLONAL HEMATOPOIESIS, FOLLOWED BY THE EMERGENCE PRELEUKEMIC STEM CELLS (PRE-LSCS). IN THIS REVIEW, WE DESCRIBE THE ROLES OF MULTIPLE INFLAMMATORY SIGNALING PATHWAYS IN THE GENERATION OF PRE-LSCS AND IN PROGRESSION TO MYELODYSPLASTIC SYNDROME (MDS), MYELOPROLIFERATIVE NEOPLASMS, AND ACUTE MYELOID LEUKEMIA (AML). IN AML, ACTIVATION OF SOME INFLAMMATORY SIGNALING PATHWAYS CAN PROMOTE THE CYCLING AND DIFFERENTIATION OF LSCS, AND THIS CAN BE EXPLOITED THERAPEUTICALLY. WE ALSO DISCUSS THE THERAPEUTIC POTENTIAL OF MODULATING INFLAMMATORY SIGNALING FOR THE TREATMENT OF MYELOID MALIGNANCIES. 2017 8 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 9 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 10 1685 24 DRUGGABLE BIOCHEMICAL PATHWAYS AND POTENTIAL THERAPEUTIC ALTERNATIVES TO TARGET LEUKEMIC STEM CELLS AND ELIMINATE THE RESIDUAL DISEASE IN CHRONIC MYELOID LEUKEMIA. CHRONIC MYELOID LEUKEMIA (CML) IS A DISEASE ARISING IN STEM CELLS EXPRESSING THE BCR-ABL ONCOGENIC TYROSINE KINASE THAT TRANSFORMS ONE HEMATOPOIETIC STEM/PROGENITOR CELL INTO A LEUKEMIC STEM CELL (LSC) AT THE ORIGIN OF DIFFERENTIATED AND PROLIFERATING LEUKEMIC CELLS IN THE BONE MARROW (BM). CML-LSCS ARE RECOGNIZED AS BEING RESPONSIBLE FOR RESISTANCES AND RELAPSES THAT OCCUR DESPITE THE ADVENT OF BCR-ABL-TARGETING THERAPIES WITH TYROSINE KINASE INHIBITORS (TKIS). LSCS SHARE A LOT OF FUNCTIONAL PROPERTIES WITH HEMATOPOIETIC STEM CELLS (HSCS) ALTHOUGH SOME PHENOTYPICAL AND FUNCTIONAL DIFFERENCES HAVE BEEN DESCRIBED DURING THE LAST TWO DECADES. SUBVERTED MECHANISMS AFFECTING EPIGENETIC PROCESSES, APOPTOSIS, AUTOPHAGY AND MORE RECENTLY METABOLISM AND IMMUNOLOGY IN THE BONE MARROW MICROENVIRONMENT (BMM) HAVE BEEN REPORTED. THE AIM OF THIS REVIEW IS TO BRING TOGETHER THE MODIFICATIONS AND MOLECULAR MECHANISMS THAT ARE KNOWN TO ACCOUNT FOR TKI RESISTANCE IN PRIMARY CML-LSCS AND TO FOCUS ON THE POTENTIAL SOLUTIONS THAT CAN CIRCUMVENT THESE RESISTANCES, IN PARTICULAR THOSE THAT HAVE BEEN, OR WILL BE TESTED IN CLINICAL TRIALS. 2019 11 570 26 BCR-ABL INDEPENDENT MECHANISMS OF RESISTANCE IN CHRONIC MYELOID LEUKEMIA. NOT ALL CHRONIC MYELOID LEUKEMIA (CML) PATIENTS ARE CURED WITH TYROSINE KINASE INHIBITORS (TKIS), AND A PROPORTION OF THEM DEVELOP RESISTANCE. RECENTLY, CONTINUOUS BCR-ABL GENE EXPRESSION HAS BEEN FOUND IN RESISTANT CELLS WITH UNDETECTABLE BCR-ABL PROTEIN EXPRESSION, INDICATING THAT RESISTANCE MAY OCCUR THROUGH KINASE INDEPENDENT MECHANISMS, MAINLY DUE TO THE PERSISTENCE OF LEUKEMIA STEM CELLS (LSCS). LSCS RESIDE IN THE BONE MARROW NICHE IN A QUIESCENT STATE, AND ARE CHARACTERIZED BY A HIGH HETEROGENEITY IN GENETIC, EPIGENETIC, AND TRANSCRIPTIONAL MECHANISMS. NEW APPROACHES BASED ON SINGLE CELL GENOMICS HAVE OFFERED THE OPPORTUNITY TO IDENTIFY DISTINCT SUBPOPULATIONS OF LSCS AT DIAGNOSIS AND DURING TREATMENT. IN THE ONE HAND, TKIS ARE NOT ABLE TO EFFICIENTLY KILL CML-LSCS, BUT THEY MAY BE RESPONSIBLE FOR THE MODIFICATION OF SOME LSCS CHARACTERISTICS, THUS CONTRIBUTING TO HETEROGENEITY WITHIN THE TUMOR. IN THE OTHER HAND, THE BONE MARROW NICHE IS RESPONSIBLE FOR THE INTERACTIONS BETWEEN SURROUNDING STROMAL CELLS AND LSCS, RESULTING IN THE GENERATION OF SPECIFIC SIGNALS WHICH COULD FAVOR LSCS CELL CYCLE ARREST AND ALLOW THEM TO PERSIST DURING TREATMENT WITH TKIS. ADDITIONALLY, LSCS MAY THEMSELVES ALTER THE NICHE BY EXPRESSING VARIOUS COSTIMULATORY MOLECULES AND SECRETING SUPPRESSIVE CYTOKINES, ABLE TO TARGET METABOLIC PATHWAYS, CREATE AN ANTI-APOPTOTIC ENVIRONMENT, AND ALTER IMMUNE SYSTEM FUNCTIONS. ACCORDINGLY, THE PRODUCTION OF AN IMMUNOSUPPRESSANT MILIEU MAY FACILITATE TUMOR ESCAPE FROM IMMUNE SURVEILLANCE AND INDUCE CHEMO-RESISTANCE. IN THIS REVIEW WE WILL FOCUS ON BCR-ABL-INDEPENDENT MECHANISMS, ANALYZING ESPECIALLY THOSE WITH A POTENTIAL CLINICAL IMPACT IN THE MANAGEMENT OF CML PATIENTS. 2019 12 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 13 359 19 ALWAYS STRESSED BUT NEVER EXHAUSTED: HOW STEM CELLS IN MYELOID NEOPLASMS AVOID EXTINCTION IN INFLAMMATORY CONDITIONS. CHRONIC OR RECURRENT EPISODES OF ACUTE INFLAMMATION CAUSE ATTRITION OF NORMAL HEMATOPOIETIC STEM CELLS (HSCS) THAT CAN LEAD TO HEMATOPOIETIC FAILURE BUT THEY DRIVE PROGRESSION IN MYELOID MALIGNANCIES AND THEIR PRECURSOR CLONAL HEMATOPOIESIS. MECHANISTIC PARALLELS EXIST BETWEEN HEMATOPOIESIS IN CHRONIC INFLAMMATION AND THE CONTINUOUSLY INCREASED PROLIFERATION OF MYELOID MALIGNANCIES, PARTICULARLY MYELOPROLIFERATIVE NEOPLASMS (MPNS). THE ABILITY TO ENTER DORMANCY, A STATE OF DEEP QUIESCENCE CHARACTERIZED BY LOW OXIDATIVE PHOSPHORYLATION, LOW GLYCOLYSIS, REDUCED PROTEIN SYNTHESIS, AND INCREASED AUTOPHAGY IS CENTRAL TO THE PRESERVATION OF LONG-TERM HSCS AND LIKELY MPN SCS. THE METABOLIC FEATURES OF DORMANCY RESEMBLE THOSE OF DIAPAUSE, A STATE OF ARRESTED EMBRYONIC DEVELOPMENT TRIGGERED BY ADVERSE ENVIRONMENTAL CONDITIONS. TO OUTCOMPETE THEIR NORMAL COUNTERPARTS IN THE INFLAMMATORY MPN ENVIRONMENT, MPN SCS CO-OPT MECHANISMS USED BY HSCS TO AVOID EXHAUSTION, INCLUDING SIGNAL ATTENUATION BY NEGATIVE REGULATORS, INSULATION FROM ACTIVATING CYTOKINE SIGNALS, ANTI-INFLAMMATORY SIGNALING, AND EPIGENETIC REPROGRAMMING. WE PROPOSE THAT NEW THERAPEUTIC STRATEGIES MAY BE DERIVED FROM CONCEPTUALIZING MYELOID MALIGNANCIES AS AN ECOSYSTEM OUT OF BALANCE, IN WHICH RESIDUAL NORMAL AND MALIGNANT HEMATOPOIETIC CELLS INTERACT IN MULTIPLE WAYS, ONLY FEW OF WHICH HAVE BEEN CHARACTERIZED IN DETAIL. DISRUPTING MPN SC INSULATION TO OVERCOME DORMANCY, INTERFERING WITH ABERRANT CYTOKINE CIRCUITS THAT FAVOR MPN CELLS, AND DIRECTLY BOOSTING RESIDUAL NORMAL HSCS ARE POTENTIAL STRATEGIES TO TIP THE BALANCE IN FAVOR OF NORMAL HEMATOPOIESIS. ALTHOUGH ERADICATING THE MALIGNANT CELL CLONES REMAINS THE GOAL OF THERAPY, REBALANCING THE ECOSYSTEM MAY BE A MORE ATTAINABLE OBJECTIVE IN THE SHORT TERM. 2023 14 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 15 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 16 5939 31 TARGETING MECHANOTRANSDUCTION AT THE TRANSCRIPTIONAL LEVEL: YAP AND BRD4 ARE NOVEL THERAPEUTIC TARGETS FOR THE REVERSAL OF LIVER FIBROSIS. LIVER FIBROSIS IS THE RESULT OF A DEREGULATED WOUND HEALING PROCESS CHARACTERIZED BY THE EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX. HEPATIC STELLATE CELLS (HSCS), WHICH ARE ACTIVATED IN RESPONSE TO LIVER INJURY, ARE THE MAJOR SOURCE OF EXTRACELLULAR MATRIX AND DRIVE THE WOUND HEALING PROCESS. HOWEVER, CHRONIC LIVER DAMAGE LEADS TO PERPETUAL HSC ACTIVATION, PROGRESSIVE FORMATION OF PATHOLOGICAL SCAR TISSUE AND ULTIMATELY, CIRRHOSIS AND ORGAN FAILURE. HSC ACTIVATION IS TRIGGERED LARGELY IN RESPONSE TO MECHANOSIGNALING FROM THE MICROENVIRONMENT, WHICH INDUCES A PROFIBROTIC NUCLEAR TRANSCRIPTION PROGRAM THAT PROMOTES HSC PROLIFERATION AND EXTRACELLULAR MATRIX SECRETION THEREBY SETTING UP A POSITIVE FEEDBACK LOOP LEADING TO MATRIX STIFFENING AND SELF-SUSTAINED, PATHOLOGICAL, HSC ACTIVATION. DESPITE THE SIGNIFICANT PROGRESS IN OUR UNDERSTANDING OF LIVER FIBROSIS, THE MOLECULAR MECHANISMS THROUGH WHICH THE EXTRACELLULAR MATRIX PROMOTES HSC ACTIVATION ARE NOT WELL UNDERSTOOD AND NO EFFECTIVE THERAPIES HAVE BEEN APPROVED TO DATE THAT CAN TARGET THIS EARLY, REVERSIBLE, STAGE IN LIVER FIBROSIS. SEVERAL NEW LINES OF INVESTIGATION NOW PROVIDE IMPORTANT INSIGHT INTO THIS AREA OF STUDY AND IDENTIFY TWO NUCLEAR TARGETS WHOSE INHIBITION HAS THE POTENTIAL OF REVERSING LIVER FIBROSIS BY INTERFERING WITH HSC ACTIVATION: YES-ASSOCIATED PROTEIN (YAP), A TRANSCRIPTIONAL CO-ACTIVATOR AND EFFECTOR OF THE MECHANOSENSITIVE HIPPO PATHWAY, AND BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4), AN EPIGENETIC REGULATOR OF GENE EXPRESSION. YAP AND BRD4 ACTIVITY IS INDUCED IN RESPONSE TO MECHANICAL STIMULATION OF HSCS AND EACH PROTEIN INDEPENDENTLY CONTROLS WAVES OF EARLY GENE EXPRESSION NECESSARY FOR HSC ACTIVATION. SIGNIFICANTLY, INHIBITION OF EITHER PROTEIN CAN REVERT THE CHRONIC ACTIVATION OF HSCS AND IMPEDE PATHOLOGICAL PROGRESSION OF LIVER FIBROSIS IN CLINICALLY RELEVANT MODEL SYSTEMS. IN THIS REVIEW WE WILL DISCUSS THE ROLES OF THESE NUCLEAR CO-ACTIVATORS IN HSC ACTIVATION, THEIR MECHANISM OF ACTION IN THE FIBROTIC PROCESS IN THE LIVER AND OTHER ORGANS, AND THE POTENTIAL OF TARGETING THEIR ACTIVITY WITH SMALL MOLECULE DRUGS FOR FIBROSIS REVERSAL. 2016 17 699 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 18 2219 30 EPIGENETIC MODIFICATIONS IN HEPATIC STELLATE CELLS CONTRIBUTE TO LIVER FIBROSIS. LIVER FIBROSIS REPRESENTS THE FINAL COMMON PATHWAY OF VIRTUALLY ALL TYPES OF CHRONIC LIVER DISEASES, AND IT HAS BEEN A MAJOR PUBLIC HEALTH CONCERN. MANY GENES HAVE BEEN DEMONSTRATED TO BE INVOLVED IN THE PATHOGENESIS OF LIVER FIBROSIS, WHILE THE MECHANISMS UNDERLYING GENE REGULATION STILL NEEDS FURTHER RESEARCH. ON THE OTHER HAND, HEPATIC STELLATE CELLS (HSCS) ARE QUIESCENT CELLS IN THE PERISINUSOIDAL SPACE IN LIVER. HSCS FACILITATE HEPATOCYTES INTERACTIONS VIA RELEASING SOLUBLE INFLAMMATORY FACTORS AND PRODUCING EXTRACELLULAR MATRIX. HSCS CAN BE ACTIVATED IN RESPONSE TO LIVER INJURY, AND THEY DIFFERENTIATE TO MYOFIBROBLASTS, WHICH GREATLY CONTRIBUTE TO THE FIBROGENESIS PROCESS. VARIOUS EPIGENETIC PROCEDURES, INCLUDING DNA METHYLATION, HISTONE MODIFICATION AND FORMATION OF PARTICULAR CHROMATIN STRUCTURE, PLAY CRUCIAL ROLES IN THE GENE TRANSCRIPTIONAL EXPRESSION IN HSCS, REGULATING VARIOUS VITAL PROCESSES. FOR INSTANCE, EPIGENETIC MODULATION ON THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA (PPAR-GAMMA) GENE PROMOTER ACCOUNTS FOR HSC DIFFERENTIATION THROUGH INTERACTING PATHWAYS. ABERRANT EXPRESSION OF A SERIES OF HISTONES AND CHEMOKINES IN ACTIVATED HSCS CAN AGGRAVATE INFLAMMATION AND OXIDATIVE STRESS, WHICH IN TURN PROMOTES DIFFERENTIATION OF HSCS TO MYOFIBROBLASTS AND ENHANCES THE WHOLE FIBROGENESIS PROCESS. DEGRADATION OF EXTRACELLULAR MATRIX IS ALSO REGULATED THROUGH EPIGENETIC MODULATION ON MATRIX ASSOCIATED ENZYMES. MOREOVER, FIBROSIS-RELATED EPIGENETIC MODIFICATIONS IN THE PARENTAL GENERATION MAY BE INHERITED TO THEIR OFFSPRING. IN THIS REVIEW, WE FIRSTLY SUMMARIZE THE VITAL EPIGENETIC MODIFICATIONS OF FIBROSIS-RELATED GENES IN HSCS, AND HIGHLIGHT SPECIFIC NUCLEIC ACID SEQUENCES AND STRUCTURES IN GENE PROMOTERS AS IMPORTANT ACTION SITES, WHICH MAY PROVIDE INDICATORS FOR LIVER FIBROSIS DIAGNOSIS IN THE FUTURE. 2013 19 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 20 4749 24 NOVEL PROSPECTS FOR SCARLESS WOUND HEALING: THE ROLES OF MYOFIBROBLASTS AND ADIPOCYTES. DISTURBANCES OR DEFECTS IN THE PROCESS OF WOUND REPAIR CAN DISRUPT THE DELICATE BALANCE OF CELLS AND MOLECULES NECESSARY FOR COMPLETE WOUND HEALING, THUS LEADING TO CHRONIC WOUNDS OR FIBROTIC SCARS. MYOFIBROBLASTS ARE ONE OF THE MOST IMPORTANT CELLS INVOLVED IN FIBROTIC SCARS, AND REPROGRAMMING PROVIDES A POTENTIAL AVENUE TO INCREASE MYOFIBROBLAST CLEARANCE. ALTHOUGH MYOFIBROBLASTS HAVE LONG BEEN RECOGNIZED AS TERMINALLY DIFFERENTIATED CELLS, RECENT STUDIES HAVE SHOWN THAT MYOFIBROBLASTS HAVE THE CAPACITY TO BE REPROGRAMMED INTO ADIPOCYTES. THIS REVIEW INTENDS TO SUMMARIZE THE POTENTIAL OF REPROGRAMMING MYOFIBROBLASTS INTO ADIPOCYTES. WE WILL DISCUSS MYOFIBROBLAST LINEAGE TRACING, AS WELL AS THE KNOWN MECHANISMS UNDERLYING ADIPOCYTE REGENERATION FROM MYOFIBROBLASTS. IN ADDITION, WE INVESTIGATED DIFFERENT CHANGES IN MYOFIBROBLAST GENE EXPRESSION, TRANSCRIPTIONAL REGULATORS, SIGNALLING PATHWAYS AND EPIGENETIC REGULATORS DURING SKIN WOUND HEALING. IN THE FUTURE, MYOFIBROBLAST REPROGRAMMING IN WOUND HEALING WILL BE BETTER UNDERSTOOD AND APPRECIATED, WHICH MAY PROVIDE NEW IDEAS FOR THE TREATMENT OF SCARLESS WOUND HEALING. 2022