Macrophage Migration Inhibitory Factor on Apoptotic Extracellular Vesicles Regulates Compensatory Proliferation

Apoptotic cells can signal to neighboring cells to stimulate proliferation and compensate for cell loss to maintain tissue homeostasis. While apoptotic cell-derived extracellular vesicles (AEVs) can transmit instructional cues to mediate communication with neighboring cells, the molecular mechanisms that induce cell division are not well understood. Here we show that macrophage migration inhibitory factor (MIF)-containing AEVs regulate compensatory proliferation via ERK signaling in epithelial stem cells of larval zebrafish. Time-lapse imaging showed efferocytosis of AEVs from dying epithelial stem cells by healthy neighboring stem cells. Proteomic and ultrastructure analysis of purified AEVs identified MIF localization on the AEV surface. Pharmacological inhibition or genetic mutation of MIF, or its cognate receptor CD74, decreased levels of phosphorylated ERK and compensatory proliferation in the neighboring epithelial stem cells. Disruption of MIF activity also caused decreased numbers of macrophages patrolling near AEVs, while depletion of the macrophage lineage resulted in a reduced proliferative response by the epithelial stem cells. We propose that AEVs carrying MIF directly stimulate epithelial stem cell repopulation and guide macrophages to cell non-autonomously induce localized proliferation to sustain overall cell numbers during tissue maintenance.

[1]  Turan Tufan,et al.  Pannexin 1 drives efficient epithelial repair after tissue injury , 2022, Science Immunology.

[2]  D. Tang,et al.  The mechanism of HMGB1 secretion and release , 2022, Experimental & Molecular Medicine.

[3]  G. T. Eisenhoffer,et al.  A protocol to evaluate epithelial regeneration after inducing cell loss in zebrafish larvae , 2022, STAR Protocols.

[4]  Y. You,et al.  Exosomal MIF Derived From Nasopharyngeal Carcinoma Promotes Metastasis by Repressing Ferroptosis of Macrophages , 2021, Frontiers in Cell and Developmental Biology.

[5]  T. Holowka,et al.  MIF but not MIF-2 recruits inflammatory macrophages in an experimental polymicrobial sepsis model. , 2021, The Journal of clinical investigation.

[6]  M. Rafat,et al.  Extracellular vesicles: mediators of intercellular communication in tissue injury and disease , 2021, Cell communication and signaling : CCS.

[7]  W.H. Tang,et al.  Exosome-mediated transfer of MIF confers temozolomide resistance by regulating TIMP3/PI3K/AKT axis in gliomas , 2021, Molecular therapy oncolytics.

[8]  J. Bernhagen,et al.  Macrophage migration inhibitory factor promotes the migration of dendritic cells through CD74 and the activation of the Src/PI3K/myosin II pathway , 2021, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[9]  Haichao Wang,et al.  Release mechanisms of major DAMPs , 2021, Apoptosis.

[10]  C. Bucci,et al.  Extracellular Vesicles and Damage-Associated Molecular Patterns: A Pandora’s Box in Health and Disease , 2020, Frontiers in Immunology.

[11]  J. Bernhagen,et al.  Revisiting the secretion mechanism(s) of macrophage migration inhibitory factor—welcome to the “UPS club” , 2020, Immunology and cell biology.

[12]  Stephanie M. George,et al.  The immune response is a critical regulator of zebrafish retinal pigment epithelium regeneration , 2020, Proceedings of the National Academy of Sciences.

[13]  Joseph M. Fernandez,et al.  A simple and effective F0 knockout method for rapid screening of behaviour and other complex phenotypes , 2020, bioRxiv.

[14]  Wenwu Zhu,et al.  Exosomes from mesenchymal stem cells overexpressing MIF enhance myocardial repair , 2020, Journal of cellular physiology.

[15]  Nan Du,et al.  Macrophage migration inhibitory factor derived from spinal cord is involved in activation of macrophages following gecko tail amputation , 2019, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[16]  L. Leng,et al.  A selective small-molecule inhibitor of macrophage migration inhibitory factor-2 (MIF-2), a MIF cytokine superfamily member, inhibits MIF-2 biological activity , 2019, The Journal of Biological Chemistry.

[17]  Nicholas A. Rossi,et al.  Inference of CRISPR Edits from Sanger Trace Data , 2019, bioRxiv.

[18]  Kornel Labun,et al.  CHOPCHOP v3: expanding the CRISPR web toolbox beyond genome editing , 2019, Nucleic Acids Res..

[19]  P. Boor,et al.  Evolving complexity of MIF signaling. , 2019, Cellular signalling.

[20]  G. T. Eisenhoffer,et al.  Stem cell proliferation is induced by apoptotic bodies from dying cells during epithelial tissue maintenance , 2019, Nature Communications.

[21]  J. Blander,et al.  On cell death in the intestinal epithelium and its impact on gut homeostasis. , 2018, Current opinion in gastroenterology.

[22]  R. Andriantsitohaina,et al.  Phenotyping of circulating extracellular vesicles (EVs) in obesity identifies large EVs as functional conveyors of Macrophage Migration Inhibitory Factor , 2018, Molecular metabolism.

[23]  E. Krupp,et al.  Automated Morphological Feature Assessment for Zebrafish Embryo Developmental Toxicity Screens , 2018, Toxicological sciences : an official journal of the Society of Toxicology.

[24]  Jong Seong Roh,et al.  Damage-Associated Molecular Patterns in Inflammatory Diseases , 2018, Immune network.

[25]  S. Shi,et al.  Circulating apoptotic bodies maintain mesenchymal stem cell homeostasis and ameliorate osteopenia via transferring multiple cellular factors , 2018, Cell Research.

[26]  D. Nam,et al.  Apoptotic Cell-Derived Extracellular Vesicles Promote Malignancy of Glioblastoma Via Intercellular Transfer of Splicing Factors. , 2018, Cancer cell.

[27]  I. Poon,et al.  Apoptotic Cell-Derived Extracellular Vesicles: More Than Just Debris , 2018, Front. Immunol..

[28]  M. Schiller,et al.  Extracellular Vesicle Subtypes Released From Activated or Apoptotic T-Lymphocytes Carry a Specific and Stimulus-Dependent Protein Cargo , 2018, Front. Immunol..

[29]  M. Bianchi,et al.  High mobility group box 1 orchestrates tissue regeneration via CXCR4 , 2018, The Journal of experimental medicine.

[30]  Fang Yao,et al.  Macrophage migration inhibitory factor (MIF) promotes rat airway muscle cell proliferation and migration mediated by ERK1/2 and FAK signaling , 2018, Cell biology international.

[31]  M. Huleihel,et al.  Production of Macrophage Inhibitory Factor (MIF) by Primary Sertoli Cells; Its Possible Involvement in Migration of Spermatogonial Cells , 2017, Journal of cellular physiology.

[32]  Z. Szondy,et al.  Anti-inflammatory Mechanisms Triggered by Apoptotic Cells during Their Clearance , 2017, Front. Immunol..

[33]  Kindra M Kelly-Scumpia,et al.  A Macrophage Response to Mycobacterium leprae Phenolic Glycolipid Initiates Nerve Damage in Leprosy , 2017, Cell.

[34]  C. Chien,et al.  A toolbox to study epidermal cell types in zebrafish , 2017, Journal of Cell Science.

[35]  T. Brunner,et al.  Cell death at the intestinal epithelial front line , 2016, The FEBS journal.

[36]  M. Robinson,et al.  Maximizing mutagenesis with solubilized CRISPR-Cas9 ribonucleoprotein complexes , 2016, Development.

[37]  R. Birge,et al.  Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer , 2016, Cell Death and Differentiation.

[38]  F. Sharif,et al.  Long‐lasting effects of dexamethasone on immune cells and wound healing in the zebrafish , 2015, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[39]  S. Mathivanan,et al.  A novel mechanism of generating extracellular vesicles during apoptosis via a beads-on-a-string membrane structure , 2015, Nature Communications.

[40]  M. Galagudza,et al.  Stimulation of Proliferation and Differentiation of Rat Resident Myocardial Cells with Apoptotic Bodies of Cardiomyocytes , 2015, Bulletin of Experimental Biology and Medicine.

[41]  Huilin Zhou,et al.  Macrophage Migration Inhibitory Factor as a Chaperone Inhibiting Accumulation of Misfolded SOD1 , 2015, Neuron.

[42]  Randall T. Moon,et al.  Macrophages modulate adult zebrafish tail fin regeneration , 2014, Development.

[43]  George M. Church,et al.  CHOPCHOP: a CRISPR/Cas9 and TALEN web tool for genome editing , 2014, Nucleic Acids Res..

[44]  Niles A. Pierce,et al.  Next-Generation in Situ Hybridization Chain Reaction: Higher Gain, Lower Cost, Greater Durability , 2014, ACS nano.

[45]  P. Asharani,et al.  Basal Keratinocytes Contribute to All Strata of the Adult Zebrafish Epidermis , 2014, PloS one.

[46]  N. Rosenthal,et al.  Macrophages are required for adult salamander limb regeneration , 2013, Proceedings of the National Academy of Sciences.

[47]  Deborah L. Thompson,et al.  The cytokine macrophage migration inhibitory factor (MIF) acts as a neurotrophin in the developing inner ear of the zebrafish, Danio rerio. , 2012, Developmental biology.

[48]  T. Wynn,et al.  Protective and pathogenic functions of macrophage subsets , 2011, Nature Reviews Immunology.

[49]  Julia L. Gregory,et al.  Macrophage Migration Inhibitory Factor and CD74 Regulate Macrophage Chemotactic Responses via MAPK and Rho GTPase , 2011, The Journal of Immunology.

[50]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[51]  Y. Wenger,et al.  Injury‐induced activation of the MAPK/CREB pathway triggers apoptosis‐induced compensatory proliferation in hydra head regeneration , 2011, Development, growth & differentiation.

[52]  Zilong Wen,et al.  Irf8 regulates macrophage versus neutrophil fate during zebrafish primitive myelopoiesis. , 2011, Blood.

[53]  A. Andrianopoulos,et al.  mpeg1 promoter transgenes direct macrophage-lineage expression in zebrafish. , 2011, Blood.

[54]  J. Bernhagen,et al.  MIF: a key player in cutaneous biology and wound healing , 2011, Experimental dermatology.

[55]  M. Hristov,et al.  Delivery of MicroRNA-126 by Apoptotic Bodies Induces CXCL12-Dependent Vascular Protection , 2009, Science Signaling.

[56]  J. Bernhagen,et al.  A functional heteromeric MIF receptor formed by CD74 and CXCR4 , 2009, FEBS letters.

[57]  J. Martinou,et al.  Apoptotic cells provide an unexpected source of Wnt3 signaling to drive hydra head regeneration. , 2009, Developmental cell.

[58]  J. Bernhagen,et al.  The Golgi-Associated Protein p115 Mediates the Secretion of Macrophage Migration Inhibitory Factor1 , 2009, The Journal of Immunology.

[59]  J. Bernhagen,et al.  Structural determinants of MIF functions in CXCR2-mediated inflammatory and atherogenic leukocyte recruitment , 2008, Proceedings of the National Academy of Sciences.

[60]  B. Noble,et al.  Apoptotic Bodies Convey Activity Capable of Initiating Osteoclastogenesis and Localized Bone Destruction , 2008, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[61]  A. Bergmann,et al.  Distinct mechanisms of apoptosis-induced compensatory proliferation in proliferating and differentiating tissues in the Drosophila eye. , 2008, Developmental cell.

[62]  B. Brüne,et al.  Tumor cell apoptosis polarizes macrophages role of sphingosine-1-phosphate. , 2007, Molecular biology of the cell.

[63]  F. McKeon,et al.  p63 Is Essential for the Proliferative Potential of Stem Cells in Stratified Epithelia , 2007, Cell.

[64]  J. Bernhagen,et al.  MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment , 2007, Nature Medicine.

[65]  Herwig Baier,et al.  Transactivation from Gal4-VP16 transgenic insertions for tissue-specific cell labeling and ablation in zebrafish. , 2007, Developmental biology.

[66]  Ryan M. Anderson,et al.  Conditional targeted cell ablation in zebrafish: A new tool for regeneration studies , 2007, Developmental dynamics : an official publication of the American Association of Anatomists.

[67]  L. Leng,et al.  Macrophage migration inhibitory factor induces MMP-9 expression in macrophages via the MEK-ERK MAP kinase pathway. , 2007, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[68]  C. Potten,et al.  An Increase in Epithelial Cell Apoptosis Is Associated with Chronic Intestinal Nematode Infection , 2007, Infection and Immunity.

[69]  L. Leng,et al.  CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex. , 2006, Immunity.

[70]  S. Zeissig,et al.  Disrupted Barrier Function through Epithelial Cell Apoptosis , 2006, Annals of the New York Academy of Sciences.

[71]  Y. Tabata,et al.  Tissue regeneration using macrophage migration inhibitory factor-impregnated gelatin microbeads in cutaneous wounds. , 2005, The American journal of pathology.

[72]  C. Gross,et al.  Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. , 2005, Cancer research.

[73]  M. Hristov,et al.  Apoptotic bodies from endothelial cells enhance the number and initiate the differentiation of human endothelial progenitor cells in vitro. , 2004, Blood.

[74]  T. Calandra,et al.  Macrophage migration inhibitory factor: a regulator of innate immunity , 2003, Nature Reviews Immunology.

[75]  J. Bernhagen,et al.  Regulated secretion of macrophage migration inhibitory factor is mediated by a non‐classical pathway involving an ABC transporter , 2003, FEBS letters.

[76]  L. Leng,et al.  MIF Signal Transduction Initiated by Binding to CD74 , 2003, The Journal of experimental medicine.

[77]  Elias Lolis,et al.  The Tautomerase Active Site of Macrophage Migration Inhibitory Factor Is a Potential Target for Discovery of Novel Anti-inflammatory Agents* , 2002, The Journal of Biological Chemistry.

[78]  D. Kimelman,et al.  A dominant-negative form of p63 is required for epidermal proliferation in zebrafish. , 2002, Developmental cell.

[79]  Lars Holmgren,et al.  Horizontal transfer of oncogenes by uptake of apoptotic bodies , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[80]  D. Ponzin,et al.  p63 identifies keratinocyte stem cells , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[81]  G. Litman,et al.  Cloning of two zebrafish cDNAs that share domains with the MHC class II-associated invariant chain , 1999, Immunogenetics.

[82]  L. Holmgren,et al.  Horizontal Transfer of DNA by the Uptake of Apoptotic Bodies , 1999, Vox sanguinis.

[83]  A. Wyllie,et al.  Apoptosis: A Basic Biological Phenomenon with Wide-ranging Implications in Tissue Kinetics , 1972, British Journal of Cancer.

[84]  B. van Steensel,et al.  Rapid Quantitative Evaluation of CRISPR Genome Editing by TIDE and TIDER. , 2019, Methods in molecular biology.

[85]  K. Ravichandran,et al.  Clearance of Dying Cells by Phagocytes: Mechanisms and Implications for Disease Pathogenesis. , 2016, Advances in experimental medicine and biology.

[86]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[87]  Ryan M. Anderson,et al.  Nitroreductase-mediated cell/tissue ablation in zebrafish: a spatially and temporally controlled ablation method with applications in developmental and regeneration studies , 2008, Nature Protocols.

[88]  D. Kimelman,et al.  Analysis of early epidermal development in zebrafish. , 2005, Methods in molecular biology.

[89]  G. Morvan-Dubois,et al.  Skin development in bony fish with particular emphasis on collagen deposition in the dermis of the zebrafish (Danio rerio). , 2004, The International journal of developmental biology.