The role of mesenchymal stem cell-derived exosome in epigenetic modifications in inflammatory diseases

Epigenetic modification is a complex process of reversible and heritable alterations in gene function, and the combination of epigenetic and metabolic alterations is recognized as an important causative factor in diseases such as inflammatory bowel disease (IBD), osteoarthritis (OA), systemic lupus erythematosus (SLE), and even tumors. Mesenchymal stem cell (MSC) and MSC-derived exosome (MSC-EXO) are widely studied in the treatment of inflammatory diseases, where they appear to be promising therapeutic agents, partly through the potent regulation of epigenetic modifications such as DNA methylation, acetylation, phosphorylation, and expression of regulatory non-coding RNAs, which affects the occurrence and development of inflammatory diseases. In this review, we summarize the current research on the role of MSC-EXO in inflammatory diseases through their modulation of epigenetic modifications and discuss its potential application in the treatment of inflammatory diseases.

[1]  Jian Wu,et al.  Histone Lactylation Boosts Reparative Gene Activation Post–Myocardial Infarction , 2022, Circulation research.

[2]  S. Ivanovski,et al.  The Relevance of DNA Methylation and Histone Modification in Periodontitis: A Scoping Review , 2022, Cells.

[3]  Xi Chen,et al.  Mesenchymal stem cell-derived exosome-educated macrophages alleviate systemic lupus erythematosus by promoting efferocytosis and recruitment of IL-17+ regulatory T cell , 2022, Stem Cell Research & Therapy.

[4]  G. Xiao,et al.  Current understanding of osteoarthritis pathogenesis and relevant new approaches , 2022, Bone Research.

[5]  H. Ishii,et al.  RNA Modification in Inflammatory Bowel Diseases , 2022, Biomedicines.

[6]  Yijun Li,et al.  MSC Promotes the Secretion of Exosomal miR-34a-5p and Improve Intestinal Barrier Function Through METTL3-Mediated Pre-miR-34A m6A Modification , 2022, Molecular Neurobiology.

[7]  Xiao-Hua Yu,et al.  Histone Deacetylase 3: A Potential Therapeutic Target for Atherosclerosis , 2022, Aging and disease.

[8]  C. Nathan.  Nonresolving inflammation redux , 2022, Immunity.

[9]  X. Su,et al.  Inhibition of DNA methylation de‐represses peroxisome proliferator‐activated receptor‐γ and attenuates pulmonary fibrosis , 2022 .

[10]  Jiawei Shao,et al.  Exosomes Derived from Mesenchymal Stem Cells Ameliorate the Progression of Atherosclerosis in ApoE−/− Mice via FENDRR , 2022, Cardiovascular Toxicology.

[11]  Lanjuan Li,et al.  Mesenchymal stem cells protect against ferroptosis via exosome-mediated stabilization of SLC7A11 in acute liver injury , 2022, Cell Death & Disease.

[12]  Y. Kluger,et al.  m6A mRNA modification maintains colonic epithelial cell homeostasis via NF-κB–mediated antiapoptotic pathway , 2022, Science advances.

[13]  Hao Wang,et al.  Lactylation-driven METTL3-mediated RNA m6A modification promotes immunosuppression of tumor-infiltrating myeloid cells. , 2022, Molecular cell.

[14]  Dongzhe Li,et al.  Mesenchymal Stem Cell Derived Exosomes Suppress Neuronal Cell Ferroptosis Via lncGm36569/miR-5627-5p/FSP1 Axis in Acute Spinal Cord Injury , 2022, Stem Cell Reviews and Reports.

[15]  Yan Tang,et al.  Crocin induces ROS-mediated papillary thyroid cancer cell apoptosis by modulating the miR-34a-5p/PTPN4 axis in vitro. , 2022, Toxicology and applied pharmacology.

[16]  J. Satsangi,et al.  Analysis of Systemic Epigenetic Alterations in Inflammatory Bowel Disease: Defining Geographical, Genetic and Immune-Inflammatory influences on the Circulating Methylome , 2021, Journal of Crohn's & colitis.

[17]  Changfeng Li,et al.  Circ_0006790 carried by bone marrow mesenchymal stem cell-derived exosomes regulates S100A11 DNA methylation through binding to CBX7 in pancreatic ductal adenocarcinoma. , 2022, American journal of cancer research.

[18]  Minzi Deng,et al.  A Broad m6A Modification Landscape in Inflammatory Bowel Disease , 2022, Frontiers in Cell and Developmental Biology.

[19]  Yong Zhang,et al.  Exosomes derived from 3D-cultured MSCs improve therapeutic effects in periodontitis and experimental colitis and restore the Th17 cell/Treg balance in inflamed periodontium , 2021, International journal of oral science.

[20]  K. McMasters,et al.  Lactate supports a metabolic-epigenetic link in macrophage polarization , 2021, Science advances.

[21]  K. Bajbouj,et al.  Histone Modification in NSCLC: Molecular Mechanisms and Therapeutic Targets , 2021, International journal of molecular sciences.

[22]  J. Lieberman,et al.  NLRP3 inflammasome activation triggers gasdermin D–independent inflammation , 2021, Science Immunology.

[23]  M. Almasian,et al.  The Impact of EGCG and RG108 on SOCS1 Promoter DNA Methylation and Expression in U937 Leukemia Cells. , 2021, Reports of biochemistry & molecular biology.

[24]  Tinghong Ye,et al.  Epigenetic regulation in fibrosis progress. , 2021, Pharmacological research.

[25]  Yanfeng Wu,et al.  TNF-α-mediated m6A modification of ELMO1 triggers directional migration of mesenchymal stem cell in ankylosing spondylitis , 2021, Nature Communications.

[26]  V. Cottin,et al.  Results of a phase 2 study of GLPG1205 for idiopathic pulmonary fibrosis (PINTA) , 2021, Idiopathic interstitial pneumonias.

[27]  Xiangdong Xu,et al.  Mesenchymal stem cell exosomal tsRNA-21109 alleviate systemic lupus erythematosus by inhibiting macrophage M1 polarization. , 2021, Molecular immunology.

[28]  X. Su,et al.  Inhibition of DNA methylation derepresses PPARγ and attenuates pulmonary fibrosis. , 2021, British journal of pharmacology.

[29]  D. Rubin,et al.  Extraintestinal Manifestations of Inflammatory Bowel Disease: Current Concepts, Treatment, and Implications for Disease Management. , 2021, Gastroenterology.

[30]  Zhen Jin,et al.  HDAC3 inhibitor suppresses endothelial-to-mesenchymal transition via modulating inflammatory response in atherosclerosis. , 2021, Biochemical pharmacology.

[31]  Q. Tu,et al.  hucMSC-derived exosomes attenuate colitis by regulating macrophage pyroptosis via the miR-378a-5p/NLRP3 axis , 2021, Stem cell research & therapy.

[32]  Yan Kang,et al.  Exosome-transported circRNA_0001236 enhances chondrogenesis and suppress cartilage degradation via the miR-3677-3p/Sox9 axis , 2021, Stem Cell Research & Therapy.

[33]  Zhiwei Xu,et al.  The Emerging Clinical Application of m6A RNA Modification in Inflammatory Bowel Disease and Its Associated Colorectal Cancer , 2021, Journal of inflammation research.

[34]  Lianna Xie,et al.  Pharmacological inhibition of EZH2 by GSK126 decreases atherosclerosis by modulating foam cell formation and monocyte adhesion in apolipoprotein E-deficient mice , 2021, Experimental and Therapeutic Medicine.

[35]  Xiaolan Zhang,et al.  A novel therapeutic approach for inflammatory bowel disease by exosomes derived from human umbilical cord mesenchymal stem cells to repair intestinal barrier via TSG-6 , 2021, Stem cell research & therapy.

[36]  Ruolan You,et al.  METTL3 mediates bone marrow mesenchymal stem cell adipogenesis to promote chemoresistance in acute myeloid leukaemia , 2021, FEBS open bio.

[37]  J. Ju,et al.  Recent Updates of Diagnosis, Pathophysiology, and Treatment on Osteoarthritis of the Knee , 2021, International journal of molecular sciences.

[38]  Hong-Qi Yang,et al.  Long non-coding RNA CIR inhibits chondrogenic differentiation of mesenchymal stem cells by epigenetically suppressing ATOH8 via methyltransferase EZH2 , 2021, Molecular medicine.

[39]  Byung-Chul Lee,et al.  Therapeutic Features and Updated Clinical Trials of Mesenchymal Stem Cell (MSC)-Derived Exosomes , 2021, Journal of clinical medicine.

[40]  E. Ballestar,et al.  Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease , 2021, Nature Communications.

[41]  F. Alcayaga-Miranda,et al.  Camouflage strategies for therapeutic exosomes evasion from phagocytosis , 2021, Journal of advanced research.

[42]  Rui Wang,et al.  TGF-β1-modified MSC-derived exosomal miR-135b attenuates cartilage injury via promoting M2 synovial macrophage polarization by targeting MAPK6 , 2021, Cell and Tissue Research.

[43]  Xu,et al.  Mesenchymal stem cell-derived exosome: The likely game-changer in stem cell research , 2021 .

[44]  Amaia Jauregi-Miguel.  The tight junction and the epithelial barrier in coeliac disease. , 2021, International review of cell and molecular biology.

[45]  Yin Tang,et al.  Overview of Histone Modification. , 2021, Advances in experimental medicine and biology.

[46]  C. June,et al.  Cytokine Storm , 2020, The New England journal of medicine.

[47]  Huiying Zhao,et al.  Epigenetic factors in atherosclerosis: DNA methylation, folic acid metabolism, and intestinal microbiota. , 2020, Clinica chimica acta; international journal of clinical chemistry.

[48]  A. Papavassiliou,et al.  Histone Methyltransferase SETDB1: A Common Denominator of Tumorigenesis with Therapeutic Potential , 2020, Cancer Research.

[49]  G. Kaplan,et al.  The four epidemiological stages in the global evolution of inflammatory bowel disease , 2020, Nature Reviews Gastroenterology & Hepatology.

[50]  Bo Qiu,et al.  Curcumin reinforces MSC‐derived exosomes in attenuating osteoarthritis via modulating the miR‐124/NF‐kB and miR‐143/ROCK1/TLR9 signalling pathways , 2020, Journal of cellular and molecular medicine.

[51]  Xiangyang Xue,et al.  Disease Activity-Associated Alteration of mRNA m5 C Methylation in CD4+ T Cells of Systemic Lupus Erythematosus , 2020, Frontiers in Cell and Developmental Biology.

[52]  Chun-Xiao Song,et al.  Mapping the epigenetic modifications of DNA and RNA , 2020, Protein & Cell.

[53]  G. Tseng,et al.  Single-Cell Analyses of Colon and Blood Reveal Distinct Immune Cell Signatures of Ulcerative Colitis and Crohn's Disease. , 2020, Gastroenterology.

[54]  Qing Sun,et al.  Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Alleviate Psoriasis-like Skin Inflammation. , 2020, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[55]  Jie Wu,et al.  Author response for "The JAK2 inhibitor AG490 regulates the Treg/Th17 balance and alleviates DSS-induced intestinal damage in IBD rats" , 2020 .

[56]  Rongpeng Yao,et al.  Exosomes derived from human umbilical cord mesenchymal stem cells ameliorate IL-6-induced acute liver injury through miR-455-3p , 2020, Stem Cell Research & Therapy.

[57]  Yongmin Yan,et al.  Human umbilical cord mesenchymal stem cells alleviate inflammatory bowel disease by inhibiting ERK phosphorylation in neutrophils , 2020, Inflammopharmacology.

[58]  Takuya Suzuki.  Regulation of the intestinal barrier by nutrients: The role of tight junctions , 2020, Animal science journal = Nihon chikusan Gakkaiho.

[59]  Ling-fen Xu,et al.  The JAK2 inhibitor AG490 regulates the Treg/Th17 balance and alleviates DSS‐induced intestinal damage in IBD rats , 2019, Clinical and experimental pharmacology & physiology.

[60]  Q. Lu,et al.  The Epigenetics of Lupus Erythematosus. , 2020, Advances in experimental medicine and biology.

[61]  Q. Lu,et al.  Epigenetics in Health and Disease. , 2020, Advances in experimental medicine and biology.

[62]  Xiaowen He,et al.  Exosomes from mesenchymal stromal cells reduce murine colonic inflammation via a macrophage-dependent mechanism. , 2019, JCI insight.

[63]  C. Khor,et al.  An intronic FTO variant rs16952570 confers protection against thiopurine-induced myelotoxicities in multiethnic Asian IBD patients , 2019, The Pharmacogenomics Journal.

[64]  J. Anolik,et al.  B cell targeted therapies in autoimmune disease. , 2019, Current opinion in immunology.

[65]  B. Ren,et al.  Metabolic regulation of gene expression by histone lactylation , 2019, Nature.

[66]  Zhenhan Deng,et al.  RhoA/ROCK pathway: implication in osteoarthritis and therapeutic targets. , 2019, American journal of translational research.

[67]  J. Mehta,et al.  Epigenetic Modification in Coronary Atherosclerosis: JACC Review Topic of the Week. , 2019, Journal of the American College of Cardiology.

[68]  C. Govind,et al.  Mesenchymal stem cells: Cell therapy and regeneration potential , 2019, Journal of tissue engineering and regenerative medicine.

[69]  G. Hawker.  Osteoarthritis is a serious disease. , 2019, Clinical and experimental rheumatology.

[70]  G. Monteleone,et al.  Inflammatory cytokines: from discoveries to therapies in IBD , 2019, Expert opinion on biological therapy.

[71]  G. Kaplan,et al.  Evolving Epidemiology of IBD , 2019, Current Gastroenterology Reports.

[72]  Chi Sun,et al.  Circulating Exosomes Derived-miR-146a from Systemic Lupus Erythematosus Patients Regulates Senescence of Mesenchymal Stem Cells , 2019, BioMed research international.

[73]  C. Hedrich,et al.  The Role of Epigenetics in Autoimmune/Inflammatory Disease , 2019, Front. Immunol..

[74]  N. Rouas-Freiss,et al.  Biological functions of mesenchymal stem cells and clinical implications , 2019, Cellular and Molecular Life Sciences.

[75]  Jinxi Wang,et al.  Epigenetic Mechanisms Underlying the Aging of Articular Cartilage and Osteoarthritis , 2019, Gerontology.

[76]  Liu Yang,et al.  miR-100-5p-abundant exosomes derived from infrapatellar fat pad MSCs protect articular cartilage and ameliorate gait abnormalities via inhibition of mTOR in osteoarthritis. , 2019, Biomaterials.

[77]  Zhihui Feng,et al.  m6A Reader YTHDF2 Regulates LPS-Induced Inflammatory Response , 2019, International journal of molecular sciences.

[78]  G. Garcia-Manero,et al.  Pracinostat plus azacitidine in older patients with newly diagnosed acute myeloid leukemia: results of a phase 2 study. , 2019, Blood advances.

[79]  M. Petri,et al.  Systemic lupus erythematosus: Diagnosis and clinical management. , 2019, Journal of autoimmunity.

[80]  M. Longworth,et al.  Epigenetics, DNA Organization, and Inflammatory Bowel Disease , 2018, Inflammatory bowel diseases.

[81]  J. Xu,et al.  [Efficacy of mesenchymal stem cells on systemic lupus erythematosus:a meta-analysis]. , 2018, Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences.

[82]  Zhen Wang,et al.  MSC-derived exosomes promote proliferation and inhibit apoptosis of chondrocytes via lncRNA-KLF3-AS1/miR-206/GIT1 axis in osteoarthritis , 2018, Cell cycle.

[83]  Vaishali R. Moulton.  Sex Hormones in Acquired Immunity and Autoimmune Disease , 2018, Front. Immunol..

[84]  Zhi-yu Huang,et al.  Exosomes derived from miR-92a-3p-overexpressing human mesenchymal stem cells enhance chondrogenesis and suppress cartilage degradation via targeting WNT5A , 2018, Stem Cell Research & Therapy.

[85]  S. Jazwinski,et al.  DNA methylation associated with healthy aging of elderly twins , 2018, GeroScience.

[86]  S. Jazwinski,et al.  DNA methylation associated with healthy aging of elderly twins , 2018, GeroScience.

[87]  Z. Qian,et al.  Overexpression of DNA (Cytosine-5)-Methyltransferase 1 (DNMT1) And DNA (Cytosine-5)-Methyltransferase 3A (DNMT3A) Is Associated with Aggressive Behavior and Hypermethylation of Tumor Suppressor Genes in Human Pituitary Adenomas , 2018, Medical science monitor : international medical journal of experimental and clinical research.

[88]  C. Relton,et al.  Age-related DNA methylation changes are tissue-specific with ELOVL2 promoter methylation as exception , 2018, Epigenetics & Chromatin.

[89]  Tom R. Gaunt,et al.  Age-related DNA methylation changes are tissue-specific with ELOVL2 promoter methylation as exception , 2018, Epigenetics & Chromatin.

[90]  Zhiguo Yuan,et al.  Mesenchymal Stem Cells in Oriented PLGA/ACECM Composite Scaffolds Enhance Structure-Specific Regeneration of Hyaline Cartilage in a Rabbit Model , 2018, Stem cells international.

[91]  A. Nelson.  Osteoarthritis year in review 2017: clinical. , 2017, Osteoarthritis and cartilage.

[92]  F. Lyko.  The DNA methyltransferase family: a versatile toolkit for epigenetic regulation , 2017, Nature Reviews Genetics.

[93]  Stephen H. Bell,et al.  A ?scoping review. , 2018, Sexual health.

[94]  Y. Naito,et al.  Gut microbiota in the pathogenesis of inflammatory bowel disease , 2018, Clinical Journal of Gastroenterology.

[95]  M. Alcaraz,et al.  Extracellular Vesicles from Adipose-Derived Mesenchymal Stem Cells Downregulate Senescence Features in Osteoarthritic Osteoblasts , 2017, Oxidative medicine and cellular longevity.

[96]  Peihui Wu,et al.  MicroRNA-92a-3p Regulates Aggrecanase-1 and Aggrecanase-2 Expression in Chondrogenesis and IL-1β-Induced Catabolism in Human Articular Chondrocytes , 2017, Cellular Physiology and Biochemistry.

[97]  Jun Pan,et al.  Alpha‐Mangostin suppresses interleukin‐1&bgr;‐induced apoptosis in rat chondrocytes by inhibiting the NF‐&kgr;B signaling pathway and delays the progression of osteoarthritis in a rat model , 2017, International immunopharmacology.

[98]  C. Hedrich.  Epigenetics in SLE , 2017, Current Rheumatology Reports.

[99]  B. Feagan,et al.  Alicaforsen for the treatment of inflammatory bowel disease , 2017, Expert opinion on investigational drugs.

[100]  G. Alarcón,et al.  Epidemiology of systemic lupus erythematosus , 2017, Expert review of clinical immunology.

[101]  A. Sawalha,et al.  Epigenetic Variability in Systemic Lupus Erythematosus: What We Learned from Genome-Wide DNA Methylation Studies , 2017, Current Rheumatology Reports.

[102]  M. Pittenger,et al.  Concise Review: MSC‐Derived Exosomes for Cell‐Free Therapy , 2017, Stem cells.

[103]  Matthew A. Cooper,et al.  Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice , 2017, Science.

[104]  D. Isenberg,et al.  The use of rituximab in newly diagnosed patients with systemic lupus erythematosus: long-term steroid saving capacity and clinical effectiveness , 2017, Lupus Science & Medicine.

[105]  D. Isenberg,et al.  263 The Use of Rituximab in Newly Diagnosed Systemic Lupus Erythematosus Patients: Long-Term Steroid-Saving Capacity and Clinical Effectiveness , 2016 .

[106]  A. Ren,et al.  Epigenetic Regulation of Osteogenic Differentiation of Mesenchymal Stem Cells. , 2016, Current stem cell research & therapy.

[107]  Dong Yun Lee,et al.  Infusion of Human Bone Marrow-Derived Mesenchymal Stem Cells Alleviates Autoimmune Nephritis in a Lupus Model by Suppressing Follicular Helper T-Cell Development , 2016, Cell transplantation.

[108]  S. Shi,et al.  MSC Transplantation Improves Osteopenia via Epigenetic Regulation of Notch Signaling in Lupus. , 2015, Cell metabolism.

[109]  T. Chan,et al.  The effect of mycophenolic acid on epigenetic modifications in lupus CD4+T cells. , 2015, Clinical immunology.

[110]  A. Gelber,et al.  Osteoarthritis , 2020, Annals of Internal Medicine.

[111]  Huidong Shi,et al.  Inhibiting DNA Methylation by 5-Aza-2'-deoxycytidine ameliorates atherosclerosis through suppressing macrophage inflammation. , 2014, Endocrinology.

[112]  F. Boudreau,et al.  The acetylome regulators Hdac1 and Hdac2 differently modulate intestinal epithelial cell dependent homeostatic responses in experimental colitis. , 2014, American journal of physiology. Gastrointestinal and liver physiology.

[113]  B. Yu,et al.  Exosomes Derived from Mesenchymal Stem Cells , 2014, International journal of molecular sciences.

[114]  L. Chamley,et al.  Human Placental Mesenchymal Stem Cells (pMSCs) Play a Role as Immune Suppressive Cells by Shifting Macrophage Differentiation from Inflammatory M1 to Anti-inflammatory M2 Macrophages , 2013, Stem Cell Reviews and Reports.

[115]  N. Kosaka,et al.  The therapeutic potential of mesenchymal stem cell‐derived extracellular vesicles , 2013, Proteomics.

[116]  Sunita M. Jain,et al.  Treatment of inflammatory bowel disease (IBD) , 2011, Pharmacological reports : PR.

[117]  J. Kolesar,et al.  Vorinostat: A novel therapy for the treatment of cutaneous T-cell lymphoma. , 2010, American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.

[118]  S. Schelling,et al.  Double-knockout of ADAMTS-4 and ADAMTS-5 in mice results in physiologically normal animals and prevents the progression of osteoarthritis. , 2007, Arthritis and rheumatism.

[119]  Shuiping Zhao,et al.  ABCG1--a potential therapeutic target for atherosclerosis. , 2007, Medical hypotheses.

[120]  G. Fantuzzi,et al.  Histone Hyperacetylation Is Associated with Amelioration of Experimental Colitis in Mice1 , 2006, The Journal of Immunology.

[121]  L. Pasquier,et al.  Orphanet Journal of Rare Diseases , 2006 .

[122]  H. Roach,et al.  Association between the abnormal expression of matrix-degrading enzymes by human osteoarthritic chondrocytes and demethylation of specific CpG sites in the promoter regions. , 2005, Arthritis and rheumatism.

[123]  Peter A. Jones,et al.  Epigenetics in human disease and prospects for epigenetic therapy , 2004, Nature.

[124]  S. Chubinskaya,et al.  Alterations in endogenous osteogenic protein‐1 with degeneration of human articular cartilage , 2003, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[125]  A. Gatherer,et al.  Sarcoma of the Larynx , 1958, The Journal of Laryngology & Otology.

[126]  E. Amento,et al.  Treating activated CD4+ T cells with either of two distinct DNA methyltransferase inhibitors, 5-azacytidine or procainamide, is sufficient to cause a lupus-like disease in syngeneic mice. , 1993, The Journal of clinical investigation.