1 5428 111 REGULATION OF STRESS-INDUCED HEMATOPOIESIS. PURPOSE OF REVIEW: THE HEMATOPOIETIC COMPARTMENT IS TASKED WITH THE ESTABLISHMENT AND MAINTENANCE OF THE ENTIRE BLOOD PROGRAM IN STEADY-STATE AND IN RESPONSE TO STRESS. KEY TO THIS PROCESS ARE HEMATOPOIETIC STEM CELLS (HSCS), WHICH POSSESS THE UNIQUE ABILITY TO SELF-RENEW AND DIFFERENTIATE TO REPLENISH BLOOD CELLS THROUGHOUT AN ORGANISM'S LIFETIME. THOUGH TIGHTLY REGULATED, THE HEMATOPOIETIC SYSTEM IS VULNERABLE TO BOTH INTRINSIC AND EXTRINSIC FACTORS THAT INFLUENCE HEMATOPOIETIC STEM AND PROGENITOR CELL (HSPC) FATE. HERE, WE REVIEW RECENT ADVANCES IN OUR UNDERSTANDING OF HEMATOPOIETIC REGULATION UNDER STRESS CONDITIONS SUCH AS INFLAMMATION, AGING, MITOCHONDRIAL DEFECTS, AND DAMAGE TO DNA OR ENDOPLASMIC RETICULUM. RECENT FINDINGS: RECENT STUDIES HAVE ILLUSTRATED THE VAST MECHANISMS INVOLVED IN REGULATING STRESS-INDUCED HEMATOPOIESIS, INCLUDING CYTOKINE-MEDIATED LINEAGE BIAS, GENE SIGNATURE CHANGES IN AGED HSCS ASSOCIATED WITH CHRONIC INFLAMMATION, THE IMPACT OF CLONAL HEMATOPOIESIS AND STRESS TOLERANCE, CHARACTERIZATION OF THE HSPC RESPONSE TO ENDOPLASMIC RETICULUM STRESS AND OF SEVERAL EPIGENETIC REGULATORS THAT INFLUENCE HSPC RESPONSE TO CELL CYCLE STRESS. SUMMARY: SEVERAL KEY RECENT FINDINGS HAVE DEEPENED OUR UNDERSTANDING OF STRESS HEMATOPOIESIS. THESE STUDIES WILL ADVANCE OUR ABILITIES TO REDUCE THE IMPACT OF STRESS IN DISEASE AND AGING THROUGH CLINICAL INTERVENTIONS TO TREAT STRESS-RELATED OUTCOMES. 2020 2 3651 32 INCREASING COMPLEXITY OF MOLECULAR LANDSCAPES IN HUMAN HEMATOPOIETIC STEM AND PROGENITOR CELLS DURING DEVELOPMENT AND AGING. THE PAST FIVE DECADES HAVE SEEN SIGNIFICANT PROGRESS IN OUR UNDERSTANDING OF HUMAN HEMATOPOIESIS. THIS HAS IN PART BEEN DUE TO THE UNPRECEDENTED DEVELOPMENT OF ADVANCED TECHNOLOGIES, WHICH HAVE ALLOWED THE IDENTIFICATION AND CHARACTERIZATION OF RARE SUBSETS OF HUMAN HEMATOPOIETIC STEM AND PROGENITOR CELLS AND THEIR LINEAGE TRAJECTORIES FROM EMBRYONIC THROUGH TO ADULT LIFE. ADDITIONALLY, SURROGATE IN VITRO AND IN VIVO MODELS, ALTHOUGH NOT FULLY RECAPITULATING HUMAN HEMATOPOIESIS, HAVE SPURRED ON THESE SCIENTIFIC ADVANCES. THESE APPROACHES HAVE HEIGHTENED OUR KNOWLEDGE OF HEMATOLOGICAL DISORDERS AND DISEASES AND HAVE LED TO THEIR IMPROVED DIAGNOSIS AND THERAPIES. HERE, WE REVIEW HUMAN HEMATOPOIESIS AT EACH END OF THE AGE SPECTRUM, DURING EMBRYONIC AND FETAL DEVELOPMENT AND ON AGING, PROVIDING EXEMPLARS OF RECENT PROGRESS IN DECIPHERING THE INCREASINGLY COMPLEX CELLULAR AND MOLECULAR HEMATOPOIETIC LANDSCAPES IN HEALTH AND DISEASE. THIS REVIEW CONCLUDES BY HIGHLIGHTING LINKS BETWEEN CHRONIC INFLAMMATION AND METABOLIC AND EPIGENETIC CHANGES ASSOCIATED WITH AGING AND IN THE DEVELOPMENT OF CLONAL HEMATOPOIESIS. 2022 3 2060 19 EPIGENETIC CONTROL OF HAEMATOPOIETIC STEM CELL AGING AND ITS CLINICAL IMPLICATIONS. AGING, CHRONIC INFLAMMATION, AND ENVIRONMENTAL INSULTS PLAY AN IMPORTANT ROLE IN A NUMBER OF DISEASE PROCESSES THROUGH ALTERATIONS OF THE EPIGENOME. IN THIS REVIEW WE EXPLORE HOW AGE-RELATED CHANGES IN THE EPIGENETIC LANDSCAPE CAN AFFECT HETEROGENEITY WITHIN THE HAEMATOPOIETIC STEM CELL (HSC) COMPARTMENT AND THE DERIVING CLINICAL IMPLICATIONS. 2016 4 5816 34 STRESS AND STEM CELLS. THE UNIQUE PROPERTIES AND FUNCTIONS OF STEM CELLS MAKE THEM PARTICULARLY SUSCEPTIBLE TO STRESSES AND ALSO LEAD TO THEIR REGULATION BY STRESS. STEM CELL DIVISION MUST RESPOND TO THE DEMAND TO REPLENISH CELLS DURING NORMAL TISSUE TURNOVER AS WELL AS IN RESPONSE TO DAMAGE. OXIDATIVE STRESS, MECHANICAL STRESS, GROWTH FACTORS, AND CYTOKINES SIGNAL STEM CELL DIVISION AND DIFFERENTIATION. MANY OF THE CONSERVED PATHWAYS REGULATING STEM CELL SELF-RENEWAL AND DIFFERENTIATION ARE ALSO STRESS-RESPONSE PATHWAYS. THE LONG LIFE SPAN AND DIVISION POTENTIAL OF STEM CELLS CREATE A PROPENSITY FOR TRANSFORMATION (CANCER) AND SPECIFIC STRESS RESPONSES SUCH AS APOPTOSIS AND SENESCENCE ACT AS ANTITUMOR MECHANISMS. QUIESCENCE REGULATED BY CDK INHIBITORS AND A HYPOXIC NICHE REGULATED BY FOXO TRANSCRIPTION FACTOR FUNCTION TO REDUCE STRESS FOR SEVERAL TYPES OF STEM CELLS TO FACILITATE LONG-TERM MAINTENANCE. AGING IS A PARTICULARLY RELEVANT STRESS FOR STEM CELLS, BECAUSE REPEATED DEMANDS ON STEM CELL FUNCTION OVER THE LIFE SPAN CAN HAVE CUMULATIVE CELL-AUTONOMOUS EFFECTS INCLUDING EPIGENETIC DYSREGULATION, MUTATIONS, AND TELOMERE EROSION. IN ADDITION, AGING OF THE ORGANISM IMPAIRS FUNCTION OF THE STEM CELL NICHE AND SYSTEMIC SIGNALS, INCLUDING CHRONIC INFLAMMATION AND OXIDATIVE STRESS. 2012 5 2592 33 EPIGENETICS OF RENAL DEVELOPMENT AND DISEASE. AN UNDERSTANDING OF EPIGENETICS IS INDISPENSABLE TO OUR UNDERSTANDING OF GENE REGULATION UNDER NORMAL AND PATHOLOGICAL STATES. THIS KNOWLEDGE WILL HELP WITH DESIGNING BETTER THERAPEUTIC APPROACHES IN REGENERATIVE TISSUE MEDICINE. EPIGENETICS ALLOWS US TO PARSE OUT THE MECHANISMS BY WHICH TRANSCRIPTIONAL REGULATORS GAIN ACCESS TO SPECIFIC GENE LOCI THEREBY IMPRINTING EPIGENETIC INFORMATION AFFECTING CHROMATIN FUNCTION. THIS EPIGENETIC MEMORY FORMS THE BASIS OF CELL LINEAGE SPECIFICATION IN MULTICELLULAR ORGANISMS. POST-TRANSLATIONAL MODIFICATIONS TO DNA AND HISTONES IN THE NUCLEOSOME CORE FORM CHARACTERISTIC EPIGENETIC CODES WHICH ARE DISTINCT FOR SELF-RENEWING AND PRIMED PROGENITOR CELL POPULATIONS. STUDIES OF CHROMATIN MODIFIERS AND MODIFICATIONS IN RENAL DEVELOPMENT AND DISEASE HAVE BEEN GAINING MOMENTUM. BOTH CONGENITAL AND ADULT RENAL DISEASES HAVE A GENE-ENVIRONMENT COMPONENT, WHICH INVOLVES ALTERATIONS TO THE EPIGENETIC INFORMATION IMPRINTED DURING DEVELOPMENT. THIS EPIGENETIC MEMORY MUST BE CHARACTERIZED TO ESTABLISH OPTIMAL TREATMENT OF BOTH ACUTE AND CHRONIC RENAL DISEASES. 2016 6 3703 27 INFLAMMATORY SIGNALLING AS MEDIATOR OF EPIGENETIC MODULATION IN TISSUE-SPECIFIC CHRONIC INFLAMMATION. RECENT SUCCESSES OF THERAPEUTIC INTERVENTION IN CHRONIC INFLAMMATORY DISEASES USING EPIGENETIC MODIFIERS SUCH AS HISTONE DEACETYLASE INHIBITORS AND INHIBITORS OF DNA METHYLATION SUGGEST THAT EPIGENETIC REPROGRAMMING PLAYS A ROLE IN THE AETIOLOGY OF THESE DISEASES. THE EPIGENETIC SIGNATURE OF A GIVEN IMMUNE CELL IS REFLECTED IN THE HISTORY OF MODIFICATIONS FROM DIFFERENT SIGNALS THE CELL HAS BEEN SUBJECTED TO DURING DIFFERENTIATION. LIKE OTHER CELLS, DIFFERENTIATING IMMUNE CELLS ARE DEPENDENT ON A COMPLEX COMBINATION OF INTER- AND INTRACELL SIGNALLING AS WELL AS TRANSCRIPTION MACHINERIES TO MODULATE THEIR EPIGENOMES IN ORDER TO MEDIATE DIFFERENTIATION. DESPITE EXTENSIVE RESEARCH INTO THESE PROCESSES, THE LINK BETWEEN CELLULAR SIGNALLING AND EPIGENETIC MODULATION REMAINS POORLY UNDERSTOOD. HERE, WE REVIEW RECENT PROGRESS AND DISCUSS KEY FACTORS DRIVING EPIGENETIC MODULATION IN CHRONIC INFLAMMATION. 2009 7 5817 22 STRESS AND THE EPIGENETIC LANDSCAPE: A LINK TO THE PATHOBIOLOGY OF HUMAN DISEASES? ACCUMULATING EVIDENCE POINTS TO A MAJOR ROLE FOR CHRONIC STRESS OF CELL RENEWAL SYSTEMS IN THE PATHOGENESIS OF IMPORTANT HUMAN DISEASES, INCLUDING CANCER, ATHEROSCLEROSIS AND DIABETES. HERE WE DISCUSS EMERGING EVIDENCE THAT EPIGENETIC ABNORMALITIES MAY MAKE SUBSTANTIAL CONTRIBUTIONS TO THESE STRESS-INDUCED PATHOLOGIES. ALTHOUGH THE MECHANISMS REMAIN TO BE FULLY ELUCIDATED, WE SUGGEST THAT CHRONIC STRESS CAN ELICIT HERITABLE CHANGES IN THE CHROMATIN LANDSCAPE THAT 'LOCK' CELLS IN ABNORMAL STATES, WHICH THEN LEAD TO DISEASE. WE EMPHASIZE THE NEED TO INVESTIGATE EPIGENETIC STATES IN DISEASE AND LINKS TO STRESS AND TO CONSIDER HOW THE KNOWLEDGE GAINED THROUGH THESE STUDIES MAY FOSTER NEW MEANS OF DISEASE PREVENTION AND MANAGEMENT. 2010 8 5410 34 REGULATION OF ADAPTIVE IMMUNE CELLS BY SIRTUINS. IT IS NOW WELL-ESTABLISHED THAT THE PATHWAYS THAT CONTROL LYMPHOCYTE METABOLISM AND FUNCTION ARE INTIMATELY LINKED, AND CHANGES IN LYMPHOCYTE METABOLISM CAN INFLUENCE AND DIRECT CELLULAR FUNCTION. INTERESTINGLY, A NUMBER OF RECENT ADVANCES INDICATE THAT LYMPHOCYTE IDENTITY AND METABOLISM IS PARTIALLY CONTROLLED VIA EPIGENETIC REGULATION. EPIGENETIC MECHANISMS, SUCH AS CHANGES IN DNA METHYLATION OR HISTONE ACETYLATION, HAVE BEEN FOUND TO ALTER IMMUNE FUNCTION AND PLAY A ROLE IN NUMEROUS CHRONIC DISEASE STATES. THERE ARE SEVERAL ENZYMES THAT CAN MEDIATE EPIGENETIC CHANGES; OF PARTICULAR INTEREST ARE SIRTUINS, PROTEIN DEACETYLASES THAT MEDIATE ADAPTIVE RESPONSES TO A VARIETY OF STRESSES (INCLUDING CALORIE RESTRICTION AND METABOLIC STRESS) AND ARE NOW UNDERSTOOD TO PLAY A SIGNIFICANT ROLE IN IMMUNITY. THIS REVIEW WILL FOCUS ON RECENT ADVANCES IN THE UNDERSTANDING OF HOW SIRTUINS AFFECT THE ADAPTIVE IMMUNE SYSTEM. THESE PATHWAYS ARE OF SIGNIFICANT INTEREST AS THERAPEUTIC TARGETS FOR THE TREATMENT OF AUTOIMMUNITY, CANCER, AND TRANSPLANT TOLERANCE. 2019 9 5581 33 ROLE OF NF-KAPPAB IN AGEING AND AGE-RELATED DISEASES: LESSONS FROM GENETICALLY MODIFIED MOUSE MODELS. AGEING IS A COMPLEX PROCESS, INDUCED BY MULTIFACETED INTERACTION OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. IT IS MANIFESTED BY A DECLINE IN THE PHYSIOLOGICAL FUNCTIONS OF ORGANISMS AND ASSOCIATED TO THE DEVELOPMENT OF AGE-RELATED CHRONIC DISEASES AND CANCER DEVELOPMENT. IT IS CONSIDERED THAT AGEING FOLLOWS A STRICTLY-REGULATED PROGRAM, IN WHICH SOME SIGNALING PATHWAYS CRITICALLY CONTRIBUTE TO THE ESTABLISHMENT AND MAINTENANCE OF THE AGED STATE. CHRONIC INFLAMMATION IS A MAJOR MECHANISM THAT PROMOTES THE BIOLOGICAL AGEING PROCESS AND COMORBIDITY, WITH THE TRANSCRIPTION FACTOR NF-KAPPAB (NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS) AS A CRUCIAL MEDIATOR OF INFLAMMATORY RESPONSES. THIS, TOGETHER WITH THE FINDING THAT THE ACTIVATION OR INHIBITION OF NF-KAPPAB CAN INDUCE OR REVERSE RESPECTIVELY THE MAIN FEATURES OF AGED ORGANISMS, HAS BROUGHT IT UNDER CONSIDERATION AS A KEY TRANSCRIPTION FACTOR THAT ACTS AS A DRIVER OF AGEING. IN THIS REVIEW, WE FOCUSED ON THE DATA OBTAINED ENTIRELY THROUGH THE GENERATION OF KNOCKOUT AND TRANSGENIC MOUSE MODELS OF EITHER PROTEIN INVOLVED IN THE NF-KAPPAB SIGNALING PATHWAY THAT HAVE PROVIDED RELEVANT INFORMATION ABOUT THE INTRICATE PROCESSES OR MOLECULAR MECHANISMS THAT CONTROL AGEING. WE HAVE REVIEWED THE RELATIONSHIP OF NF-KAPPAB AND PREMATURE AGEING; THE DEVELOPMENT OF CANCER ASSOCIATED WITH AGEING AND THE IMPLICATION OF NF-KAPPAB ACTIVATION IN THE DEVELOPMENT OF AGE-RELATED DISEASES, SOME OF WHICH GREATLY INCREASE THE RISK OF DEVELOPING CANCER. 2021 10 1923 16 ENVIRONMENTAL EPIGENETIC MODIFICATIONS AND REPROGRAMMING-RECALCITRANT GENES. THE TERM "ENVIRONMENTAL EPIGENETIC MODIFICATIONS" REFERS TO ALTERATIONS IN PHENOTYPE TRIGGERED BY ENVIRONMENTAL STIMULI VIA EPIGENETIC MECHANISMS. EPIDEMIOLOGIC AND ANIMAL MODEL STUDIES SHOW THAT A SUBSET OF SUCH ENVIRONMENTAL EPIGENETIC MARKS MAY AFFECT SUSCEPTIBILITY TO CHRONIC DISEASES. A GROWING BODY OF EVIDENCE REGARDING INCOMPLETENESS OF REPROGRAMMING INDICATES THAT THE POTENTIAL RETENTION OF PATHOGENIC ENVIRONMENTAL EPIGENETICS IN HUMAN INDUCED PLURIPOTENT STEM CELLS (IPSCS) SHOULD BE SERIOUSLY CONSIDERED. GIVEN THIS POSSIBILITY, THE OPTIMIZATION OF METHODS FOR THE GENERATION OF HUMAN INDUC PLURIPOTENT STEM CELLS MAY REQUIRE THE IDENTIFICATION OF EPIGENETICALLY APPROPRIATE SOMATIC CELL SOURCES. SIMILARLY, TECHNIQUES FOR CONTROLLING EPIGENETIC MODIFICATION BY ENVIRONMENTAL FACTORS MAY ALSO PLAY A CRITICAL ROLE IN THE DEVELOPMENT OF EPIGENETICALLY STABLE SOURCES OF PLURIPOTENT STEM CELLS. 2010 11 733 31 CANCER EPIGENETICS: LINKING BASIC BIOLOGY TO CLINICAL MEDICINE. CANCER EVOLUTION AT ALL STAGES IS DRIVEN BY BOTH EPIGENETIC ABNORMALITIES AS WELL AS GENETIC ALTERATIONS. DYSREGULATION OF EPIGENETIC CONTROL EVENTS MAY LEAD TO ABNORMAL PATTERNS OF DNA METHYLATION AND CHROMATIN CONFIGURATIONS, BOTH OF WHICH ARE CRITICAL CONTRIBUTORS TO THE PATHOGENESIS OF CANCER. THESE EPIGENETIC ABNORMALITIES ARE SET AND MAINTAINED BY MULTIPLE PROTEIN COMPLEXES AND THE INTERPLAY BETWEEN THEIR INDIVIDUAL COMPONENTS INCLUDING DNA METHYLATION MACHINERY, HISTONE MODIFIERS, PARTICULARLY, POLYCOMB (PCG) PROTEINS, AND CHROMATIN REMODELING PROTEINS. RECENT ADVANCES IN GENOME-WIDE TECHNOLOGY HAVE REVEALED THAT THE INVOLVEMENT OF THESE DYSREGULATED EPIGENETIC COMPONENTS APPEARS TO BE EXTENSIVE. MOREOVER, THERE IS A GROWING CONNECTION BETWEEN EPIGENETIC ABNORMALITIES IN CANCER AND CONCEPTS CONCERNING STEM-LIKE CELL SUBPOPULATIONS AS A DRIVING FORCE FOR CANCER. EMERGING DATA SUGGEST THAT ASPECTS OF THE EPIGENETIC LANDSCAPE INHERENT TO NORMAL EMBRYONIC AND ADULT STEM/PROGENITOR CELLS MAY HELP FOSTER, UNDER THE STRESS OF CHRONIC INFLAMMATION OR ACCUMULATING REACTIVE OXYGEN SPECIES, EVOLUTION OF MALIGNANT SUBPOPULATIONS. FINALLY, UNDERSTANDING MOLECULAR MECHANISMS INVOLVED IN INITIATION AND MAINTENANCE OF EPIGENETIC ABNORMALITIES IN ALL TYPES OF CANCER HAS GREAT POTENTIAL FOR TRANSLATIONAL PURPOSES. THIS IS ALREADY EVIDENT FOR EPIGENETIC BIOMARKER DEVELOPMENT, AND FOR PHARMACOLOGICAL TARGETING AIMED AT REVERSING CANCER-SPECIFIC EPIGENETIC ALTERATIONS. 2011 12 2416 26 EPIGENETIC SIGNALING OF CANCER STEM CELLS DURING INFLAMMATION. MALIGNANT TUMORS POSE A GREAT CHALLENGE TO HUMAN HEALTH, WHICH HAS LED TO MANY STUDIES INCREASINGLY ELUCIDATING THE TUMORIGENIC PROCESS. CANCER STEM CELLS (CSCS) HAVE PROFOUND IMPACTS ON TUMORIGENESIS AND DEVELOPMENT OF DRUG RESISTANCE. RECENTLY, THERE HAS BEEN INCREASED INTEREST IN THE RELATIONSHIP BETWEEN INFLAMMATION AND CSCS BUT THE MECHANISM UNDERLYING THIS RELATIONSHIP HAS NOT BEEN FULLY ELUCIDATED. INFLAMMATORY CYTOKINES PRODUCED DURING CHRONIC INFLAMMATION ACTIVATE SIGNALING PATHWAYS THAT REGULATE THE GENERATION OF CSCS THROUGH EPIGENETIC MECHANISMS. IN THIS REVIEW, WE FOCUS ON THE EFFECTS OF INFLAMMATION ON CANCER STEM CELLS, PARTICULARLY THE ROLE OF SIGNALING PATHWAYS SUCH AS NF-KAPPAB PATHWAY, STAT3 PATHWAY AND SMAD PATHWAY INVOLVED IN REGULATING EPIGENETIC CHANGES. WE HOPE TO PROVIDE A NOVEL PERSPECTIVE FOR IMPROVING STRATEGIES FOR TUMOR TREATMENT. 2021 13 3123 31 GETTING AN INSIGHT INTO THE COMPLEXITY OF MAJOR CHRONIC INFLAMMATORY AND DEGENERATIVE DISEASES: A POTENTIAL NEW SYSTEMIC APPROACH TO THEIR TREATMENT. AS THE MODERN SOCIETY IS TROUBLED BY MULTI-FACTORIAL DISEASES, RESEARCH HAS BEEN CONDUCTED ON COMPLEX REALITIES INCLUDING CHRONIC INFLAMMATION, CANCER, OBESITY, HIV INFECTION, METABOLIC SYNDROME AND ITS DETRIMENTAL CARDIOVASCULAR COMPLICATIONS AS WELL AS DEPRESSION AND OTHER BRAIN DISORDERS. DETERIORATION OF CRUCIAL HOMEOSTATIC MECHANISMS IN SUCH DISEASES INVARIABLY RESULTS IN ACTIVATION OF INFLAMMATORY MEDIATORS, CHRONIC INFLAMMATION, LOSS IN IMMUNOLOGICAL FUNCTION, INCREASED SUSCEPTIBILITY TO DISEASES, ALTERATION OF METABOLISM, DECREASE OF ENERGY PRODUCTION AND NEURO-COGNITIVE DECLINE. REGULATION OF GENES EXPRESSION BY EPIGENETIC CODE IS THE DOMINANT MECHANISM FOR THE TRANSDUCTION OF ENVIRONMENTAL INPUTS, SUCH AS STRESS AND INFLAMMATION TO LASTING PHYSIOLOGICAL CHANGES. ACUTE AND CHRONIC STRESS DETERMINES DNA METHYLATION AND HISTONE MODIFICATIONS IN BRAIN REGIONS WHICH MAY CONTRIBUTE TO NEURO-DEGENERATIVE DISORDERS. NUCLEAR GLUCOCORTICOIDS RECEPTOR INTERACTS WITH THE EPIGENOMA RESULTING IN A CORTISOL RESISTANCE STATUS ASSOCIATED WITH A DETERIORATION OF THE METABOLIC AND IMMUNE FUNCTIONS. GONADAL STEROIDS RECEPTORS HAVE A SIMILAR CAPACITY TO PRODUCE EPIGENOMIC REORGANIZATION OF CHROMATINE STRUCTURE. EPIGENOMIC-INDUCED REDUCTION IN IMMUNE CELLS TELOMERES LENGTH HAS BEEN OBSERVED IN MANY DEGENERATIVE DISEASES, INCLUDING ALL TYPES OF CANCER. THE FINAL RESULT OF THESE EPIGENETIC ALTERATIONS IS A SERIOUS DAMAGE TO THE NEURO-ENDOCRINE-IMMUNE-METABOLIC ADAPTIVE SYSTEMS. IN THIS STUDY, WE PROPOSE A TREATMENT WITH STEM CELLS DIFFERENTIATION STAGE FACTORS TAKEN FROM ZEBRAFISH EMBRYOS WHICH ARE ABLE TO REGULATE THE GENES EXPRESSION OF NORMAL AND PATHOLOGICAL STEM CELLS IN A DIFFERENT SPECIFIC WAY. 2015 14 2174 31 EPIGENETIC MECHANISMS INVOLVED IN MODULATION OF INFLAMMATORY DISEASES. PURPOSE OF REVIEW: THE ACTIVATION OF INFLAMMATORY RESPONSE IS DEPENDENT UPON GENETIC FACTORS AND EPIGENETIC CONTROL MECHANISMS. THIS OVERVIEW WILL HIGHLIGHT RECENT ADVANCES IN THE UNDERSTANDING OF EPIGENETIC DYNAMICS DURING CELLULAR INFLAMMATION. RECENT FINDINGS: THERE IS A GROWING BODY OF EVIDENCE INDICATING THAT ALTERATIONS OF THE CHROMATIN STATE ASSOCIATE WITH AN INCREASED RISK OF CHRONIC DISEASE DEVELOPMENT AND INFLAMMATION. EPIGENETIC ALTERATIONS RESPOND RAPIDLY TO ENVIRONMENTAL CHANGES AND HAVE A PROFOUND EFFECT ON GENE REGULATORY CROSS-WIRINGS AND TRANSCRIPTIONAL REGULATION. SUMMARY: SYSTEMATIC DISSECTION OF THE MECHANISMS UNDERLYING EPIGENETIC EFFECTS DURING INFLAMMATORY RESPONSE IS A CRITICAL STEP TOWARD ELUCIDATION OF THE CELL'S MOLECULAR PROCESSES AND HOLDS POTENTIAL FOR THE DEVELOPMENT OF NOVEL THERAPIES FOR THE TREATMENT OF CHRONIC DISEASES. 2016 15 6213 27 THE INTESTINAL EPITHELIAL CELL CYCLE: UNCOVERING ITS 'CRYPTIC' NATURE. PURPOSE OF REVIEW: TO DISCUSS THE RECENT LANDMARK FINDINGS THAT HAVE INCREASED OUR UNDERSTANDING NOT ONLY OF THE ROLE OF THE EPITHELIAL CELL CYCLE IN THE HOMEOSTASIS OF THE SMALL INTESTINE, BUT ALSO ITS RELEVANCE TO INFLAMMATION AND CANCER. RECENT FINDINGS: RECENT DATA HAVE UNVEILED NOVEL INFORMATION ON PROTEIN INTERACTIONS DIRECTLY INVOLVED IN THE CELL CYCLE AS WELL AS IN THE PATHWAYS THAT TRANSDUCE EXTERNAL ENVIRONMENTAL SIGNALS TO THE CELL CYCLE. A GROWING BODY OF THE RECENT EVIDENCE CONFIRMS THE IMPORTANCE OF FOOD AS WELL AS HORMONAL REGULATION IN THE GUT ON CELL CYCLE. INFORMATION ON THE CONTRIBUTION OF THE EPITHELIAL MICROENVIRONMENT, INCLUDING THE MICROBIOTA, HAS GROWN SUBSTANTIALLY IN THE RECENT YEARS AS WELL AS ON THE GENE-ENVIRONMENT INTERACTIONS AND THE MULTIPLE EPIGENETIC MECHANISMS INVOLVED IN REGULATING CELL-CYCLE PROTEINS AND SIGNALLING. FINALLY, FURTHER STUDIES INVESTIGATING THE DYSREGULATION OF THE CELL CYCLE DURING INFLAMMATION AND PROLIFERATION HAVE INCREASED OUR UNDERSTANDING OF THE PATHOPHYSIOLOGY OF CHRONIC INFLAMMATORY DISEASES AND CANCER. SUMMARY: THIS REVIEW HIGHLIGHTS SOME OF THE MOST RECENT ADVANCES THAT FURTHER EMPHASIZE THE IMPORTANCE OF THE CELL CYCLE IN THE SMALL INTESTINE DURING HOMEOSTASIS AS WELL AS IN INFLAMMATION AND CANCER. 2015 16 6344 30 THE ROLE OF EPIGENETICS IN AGING AND AUTOIMMUNITY. THE DECLINE IN IMMUNOCOMPETENCE WITH AGE IS ACCOMPANIED BY THE INCREASE IN THE INCIDENCE OF AUTOIMMUNE DISEASES. AGING OF THE IMMUNE SYSTEM, OR IMMUNOSENESCENCE, IS CHARACTERIZED BY A DECLINE OF BOTH T AND B CELL FUNCTION, AND PARADOXICALLY THE PRESENCE OF LOW-GRADE CHRONIC INFLAMMATION. THERE IS GROWING EVIDENCE THAT EPIGENETICS, THE STUDY OF INHERITED CHANGES IN GENE EXPRESSION THAT ARE NOT ENCODED BY THE DNA SEQUENCE ITSELF, CHANGES WITH AGING. INTERESTINGLY, EMERGING EVIDENCE SUGGESTS A KEY ROLE FOR EPIGENETICS IN HUMAN PATHOLOGIES, INCLUDING INFLAMMATORY AND NEOPLASTIC DISORDERS. HERE, WE WILL REVIEW THE POTENTIAL MECHANISMS THAT CONTRIBUTE TO THE INCREASE IN AUTOIMMUNE RESPONSES IN AGING. IN PARTICULAR, WE WILL DISCUSS HOW EPIGENETIC ALTERATIONS, ESPECIALLY DNA METHYLATION AND HISTONE ACETYLATION, ARE ACCUMULATED DURING AGING AND HOW THESE EVENTS CONTRIBUTE TO AUTOIMMUNITY RISK. 2010 17 6244 33 THE MECHANISMS OF HSC ACTIVATION AND EPIGENETIC REGULATION OF HSCS PHENOTYPES. EPIGENETICS IS A DYNAMICALLY EXPANDING FIELD OF SCIENCE ENTAILING NUMEROUS REGULATORY MECHANISMS CONTROLLING CHANGES OF GENE EXPRESSION IN RESPONSE TO ENVIRONMENTAL FACTORS. OVER THE RECENT YEARS THERE HAS BEEN A GREAT INTEREST IN EPIGENETIC MARKS AS A POTENTIAL DIAGNOSTIC AND PROGNOSTIC TOOL OR FUTURE TARGET FOR TREATMENT OF VARIOUS HUMAN DISEASES. THERE IS AN INCREASING BODY OF PUBLISHED RESEARCH TO SUGGEST THAT EPIGENETIC EVENTS REGULATE PROGRESSION OF CHRONIC LIVER DISEASE. EXPERIMENTAL MANIPULATION OF EPIGENETIC SIGNATURES SUCH AS DNA METHYLATION, HISTONE ACETYLATION / METHYLATION AND THE ACTIVITIES OF PROTEINS THAT EITHER ANNOTATE OR INTERPRET THESE EPIGENETIC MARKS CAN HAVE PROFOUND EFFECTS ON THE ACTIVATION AND PHENOTYPE OF HSC, KEY CELLS RESPONSIBLE FOR ONSET AND PROGRESSION OF LIVER FIBROSIS. THIS REVIEW PRESENTS RECENT ADVANCES IN EPIGENETIC ALTERATIONS, WHICH COULD PROVIDE MECHANISTIC INSIGHT INTO THE PATHOGENESIS OF CHRONIC LIVER DISEASE AND PROVIDE NOVEL CLINICAL APPLICATIONS. 2014 18 389 24 AN INTEGRATIVE HYPOTHESIS LINKING CANCER, DIABETES AND ATHEROSCLEROSIS: THE ROLE OF MUTATIONS AND EPIGENETIC CHANGES. IT APPEARS THAT THE DISEASE STATES OF CANCER, ALTHEROSCLEROSIS AND DIABETES MIGHT SHARE A COMMON ETIOLOGY. THESE CHRONIC DISEASES APPEAR TO BE MULTI-STAGED IN THEIR PROGRESSION, WITH GENETIC, NUTRITIONAL, PSYCHO-SOCIAL, ENVIRONMENTAL AND VIRAL FACTORS INFLUENCING THEIR APPEARANCE. WE OFFERED A HYPOTHESIS (A "MUTATION THEORY OF DISEASE"), STATING THAT THESE DISEASES CAN BE DESCRIBED BY INITIATION AND PROMOTION PHASES; INITIATION BEING THE RESULT OF THE PRODUCTION OF MUTATED CELLS AFTER UNREPAIRED DAMAGED DNA IS REPLICATED; PROMOTION BEING THE SELECTIVE PROLIFERATION OF THE INITIATED CELLS TO FORM CLONES OF MUTATED CELLS. IT WAS FURTHER POSTULATED THAT PROMOTION AFFECTS CELL PROLIFERATION BY ALTERING A MEMBRANE-CA++ REGULATORY SYSTEM. DEPENDING ON THE NATURE OF THE MUTATION IN THE CLONE OF CELLS, SPECIFIC DISEASE STATES WOULD RESULT. THE ROLES OF RADIATIONS, CHEMICALS, VIRUSES, GENES, NUTRITION AND PSYCHO-SOCIAL STRESS WERE RELATED TO EITHER THE INITIATION (MUTATION PRODUCTION) OR THE PROMOTION (CELL PROLIFERATION) PHASE OF THESE DISEASES. 1980 19 5798 33 STEM CELLS AND LUNG REGENERATION. THE ABILITY TO REPLACE DEFECTIVE CELLS IN AN AIRWAY WITH CELLS THAT CAN ENGRAFT, INTEGRATE, AND RESTORE A FUNCTIONAL EPITHELIUM COULD POTENTIALLY CURE A NUMBER OF LUNG DISEASES. PROGRESS TOWARD THE DEVELOPMENT OF STRATEGIES TO REGENERATE THE ADULT LUNG BY EITHER IN VIVO OR EX VIVO TARGETING OF ENDOGENOUS STEM CELLS OR PLURIPOTENT STEM CELL DERIVATIVES IS LIMITED BY OUR FUNDAMENTAL LACK OF UNDERSTANDING OF THE MECHANISMS CONTROLLING HUMAN LUNG DEVELOPMENT, THE PRECISE IDENTITY AND FUNCTION OF HUMAN LUNG STEM AND PROGENITOR CELL TYPES, AND THE GENETIC AND EPIGENETIC CONTROL OF HUMAN LUNG FATE. IN THIS REVIEW, WE INTEND TO DISCUSS THE KNOWN STEM/PROGENITOR CELL POPULATIONS, THEIR RELATIVE DIFFERENCES BETWEEN RODENTS AND HUMANS, THEIR ROLES IN CHRONIC LUNG DISEASE, AND THEIR THERAPEUTIC PROSPECTS. ADDITIONALLY, WE HIGHLIGHT THE RECENT BREAKTHROUGHS THAT HAVE INCREASED OUR UNDERSTANDING OF THESE CELL TYPES. THESE ADVANCEMENTS INCLUDE NOVEL LINEAGE-TRACED ANIMAL MODELS AND SINGLE-CELL RNA SEQUENCING OF HUMAN AIRWAY CELLS, WHICH HAVE PROVIDED CRITICAL INFORMATION ON THE STEM CELL SUBTYPES, TRANSITION STATES, IDENTIFYING CELL MARKERS, AND INTRICATE PATHWAYS THAT COMMIT A STEM CELL TO DIFFERENTIATE OR TO MAINTAIN PLASTICITY. AS OUR CAPACITY TO MODEL THE HUMAN LUNG EVOLVES, SO WILL OUR UNDERSTANDING OF LUNG REGENERATION AND OUR ABILITY TO TARGET ENDOGENOUS STEM CELLS AS A THERAPEUTIC APPROACH FOR LUNG DISEASE. 2020 20 115 26 A STEM CELL AGING FRAMEWORK, FROM MECHANISMS TO INTERVENTIONS. STEM CELLS PLAY CENTRAL ROLES IN TISSUE DEVELOPMENT, HOMEOSTASIS, AND REGENERATION. DECADES OF SCIENTIFIC RESEARCH HAVE UNCOVERED PROCESSES OF STEM CELL DECLINE IN TISSUE AND ORGANISMAL AGING, AND MORE RECENTLY, PIONEERING TECHNOLOGIES PERMIT THE DISSECTION OF ITS UNDERLYING MECHANISMS AND INFORM THERAPEUTIC DEVELOPMENT FOR AGING AND AGING-ASSOCIATED DISORDERS. IN THIS REVIEW, WE ELUCIDATE AGING-RELATED FEATURES ACROSS DIFFERENT SOMATIC STEM CELL TYPES, WITH A SPECIFIC FOCUS ON EPIGENETIC CHANGES, LOSS OF PROTEIN HOMEOSTASIS, AND SYSTEMIC INFLUENCING FACTORS, INCLUDING CHRONIC INFLAMMATION, CIRCADIAN RHYTHM DYSREGULATION, AND METABOLIC DISORDER. OUR SURVEY OF ORGANISMAL STEM CELL AGING SUMMARIZES ITS UNDERLYING BIOLOGICAL IMPLICATIONS, POINTS TO POTENTIAL BIOMARKERS OF STEM CELL AGING, AND DISCUSSES STEM CELL-BASED THERAPEUTIC STRATEGIES WITH THE POTENTIAL FOR PROMOTING HEALTHY AGING AND COMBATING AGING AND AGE-RELATED DISEASES. 2022