LIF signaling in stem cells and development

Leukemia inhibitory factor (LIF) is a member of the interleukin-6 (IL-6) cytokine family. All members of this family activate signal transducer and activator of transcription 3 (STAT3), a transcription factor that influences stem and progenitor cell identity, proliferation and cytoprotection. The role of LIF in development was first identified when LIF was demonstrated to support the propagation of mouse embryonic stem cells. Subsequent studies of mice deficient for components of the LIF pathway have revealed important roles for LIF signaling during development and homeostasis. Here and in the accompanying poster, we provide a broad overview of JAK-STAT signaling during development, with a specific focus on LIF-mediated JAK-STAT3 activation. Summary: This poster article provides an overview of the LIF-JAK-STAT signalling pathway and discusses how this pathway functions in stem cells and early development.

[1]  C. Thut,et al.  Leukemia inhibitory factor receptor is structurally related to the IL‐6 signal transducer, gp130. , 1991, The EMBO journal.

[2]  Sara G. Becker-Catania,et al.  A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis , 2005, Nature Neuroscience.

[3]  N. Nakatsuji,et al.  Functional requirement of gp130-mediated signaling for growth and survival of mouse primordial germ cells in vitro and derivation of embryonic germ (EG) cells. , 1996, Development.

[4]  David M. Umulis,et al.  The extracellular regulation of bone morphogenetic protein signaling , 2009, Development.

[5]  I. Amit,et al.  Derivation of novel human ground state naive pluripotent stem cells , 2013, Nature.

[6]  K. Miyazono,et al.  Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. , 1999, Science.

[7]  J. Marine,et al.  Jak2 Is Essential for Signaling through a Variety of Cytokine Receptors , 1998, Cell.

[8]  F. Brook,et al.  The origin and efficient derivation of embryonic stem cells in the mouse. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[9]  P Jay,et al.  Specific inhibition of Stat3 signal transduction by PIAS3. , 1997, Science.

[10]  M. Welham,et al.  Regulation of Embryonic Stem Cell Self-renewal by Phosphoinositide 3-Kinase-dependent Signaling* , 2004, Journal of Biological Chemistry.

[11]  B. Hogan,et al.  Bmp4 is required for the generation of primordial germ cells in the mouse embryo. , 1999, Genes & development.

[12]  J. Thomson,et al.  Isolation of a primate embryonic stem cell line. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Austin G Smith,et al.  Stat3 Activation Is Limiting for Reprogramming to Ground State Pluripotency , 2010, Cell stem cell.

[14]  H. Schöler,et al.  Induction of pluripotency in adult unipotent germline stem cells. , 2009, Cell stem cell.

[15]  S. Akira,et al.  Structure and function of a new STAT-induced STAT inhibitor , 1997, Nature.

[16]  Donald Metcalf,et al.  Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells , 1988, Nature.

[17]  C. Brannan,et al.  Requirement for mast cell growth factor for primordial germ cell survival in culture , 1991, Nature.

[18]  K. Shiota,et al.  Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[19]  M. Oshimura,et al.  Generation of Pluripotent Stem Cells from Neonatal Mouse Testis , 2004, Cell.

[20]  M. Van Doren,et al.  Jak-STAT regulation of male germline stem cell establishment during Drosophila embryogenesis. , 2009, Developmental biology.

[21]  K. Zsebo,et al.  Effects of the steel gene product on mouse primordial germ cells in culture , 1991, Nature.

[22]  Austin G Smith,et al.  Capture of Authentic Embryonic Stem Cells from Rat Blastocysts , 2008, Cell.

[23]  C. Stewart,et al.  Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor , 1992, Nature.

[24]  H. Ohta,et al.  Reconstitution of the Mouse Germ Cell Specification Pathway in Culture by Pluripotent Stem Cells , 2011, Cell.

[25]  M. Azim Surani,et al.  SOX17 Is a Critical Specifier of Human Primordial Germ Cell Fate , 2015, Cell.

[26]  L. C. Stevens The development of transplantable teratocarcinomas from intratesticular grafts of pre- and postimplantation mouse embryos. , 1970, Developmental biology.

[27]  H. Ohta,et al.  A Signaling Principle for the Specification of the Germ Cell Lineage in Mice , 2009, Cell.

[28]  G. Martin,et al.  Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[29]  Qi Zhou,et al.  Dissecting Signaling Pathways That Govern Self-renewal of Rabbit Embryonic Stem Cells* , 2008, Journal of Biological Chemistry.

[30]  T. Hirano,et al.  Molecular cloning and expression of an IL-6 signal transducer, gp130 , 1990, Cell.

[31]  Herbert Schulz,et al.  Novel STAT3 Target Genes Exert Distinct Roles in the Inhibition of Mesoderm and Endoderm Differentiation in Cooperation with Nanog , 2009, Stem cells.

[32]  P. Zandstra,et al.  Local BMP-SMAD1 Signaling Increases LIF Receptor-Dependent STAT3 Responsiveness and Primed-to-Naive Mouse Pluripotent Stem Cell Conversion Frequency , 2014, Stem cell reports.

[33]  S. Nishikawa,et al.  Effect of Steel factor and leukaemia inhibitory factor on murine primordial germ cells in culture , 1991, Nature.

[34]  F. Brook,et al.  Reflections on the biology of embryonic stem (ES) cells. , 1997, The International journal of developmental biology.

[35]  M. Kaufman,et al.  Establishment in culture of pluripotential cells from mouse embryos , 1981, Nature.

[36]  S. Akira,et al.  Keratinocyte‐specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis , 1999, The EMBO journal.

[37]  S. Akira,et al.  Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. , 1998, Journal of immunology.

[38]  D. Levy,et al.  What does Stat3 do? , 2002, The Journal of clinical investigation.

[39]  A. Dunn,et al.  gp130-mediated Signal Transduction in Embryonic Stem Cells Involves Activation of Jak and Ras/Mitogen-activated Protein Kinase Pathways* , 1996, The Journal of Biological Chemistry.

[40]  S. S. Zhang,et al.  Cardiomyocyte-restricted knockout of STAT3 results in higher sensitivity to inflammation, cardiac fibrosis, and heart failure with advanced age , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[41]  J. Thomson,et al.  Embryonic stem cell lines derived from human blastocysts. , 1998, Science.

[42]  S. Akira,et al.  Correction: Stat3 Activation Is Responsible for IL-6–Dependent T Cell Proliferation through Preventing Apoptosis: Generation and Characterization of T Cell–Specific Stat3-Deficient Mice , 2015, The Journal of Immunology.

[43]  John K. Heath,et al.  Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides , 1988, Nature.

[44]  P. Zandstra,et al.  Microenvironment-mediated reversion of epiblast stem cells by reactivation of repressed JAK-STAT signaling. , 2012, Integrative biology : quantitative biosciences from nano to macro.

[45]  R. Pedersen,et al.  Activin/Nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells , 2005, Journal of Cell Science.

[46]  T. Blauwkamp,et al.  Embryonic stem cells require Wnt proteins to prevent differentiation to epiblast stem cells , 2011, Nature Cell Biology.

[47]  Qi-Long Ying,et al.  Gbx2, a LIF/Stat3 target, promotes reprogramming to and retention of the pluripotent ground state , 2013, Journal of Cell Science.

[48]  D. Levy,et al.  What does Stat 3 do ? , 2002 .

[49]  J. Nichols,et al.  Suppression of SHP-2 and ERK signalling promotes self-renewal of mouse embryonic stem cells. , 1999, Developmental biology.

[50]  Guoji Guo,et al.  A genetic and developmental pathway from STAT3 to the OCT4-NANOG circuit is essential for maintenance of ICM lineages in vivo. , 2013, Genes & development.

[51]  M. Greenberg,et al.  Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway. , 1997, Science.

[52]  R. Schreiber,et al.  Disruption of the Jak1 Gene Demonstrates Obligatory and Nonredundant Roles of the Jaks in Cytokine-Induced Biologic Responses , 1998, Cell.

[53]  P. Donovan,et al.  Long-term proliferation of mouse primordial germ cells in culture , 1992, Nature.

[54]  M. Katsuki,et al.  STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells , 1999, The EMBO journal.

[55]  Hsu-hsin Chen,et al.  A murine ESC-like state facilitates transgenesis and homologous recombination in human pluripotent stem cells. , 2010, Cell stem cell.

[56]  L. C. Stevens,et al.  Spontaneous Testicular Teratomas in an Inbred Strain of Mice. , 1954, Proceedings of the National Academy of Sciences of the United States of America.

[57]  H. Ka,et al.  Primed Pluripotent Cell Lines Derived from Various Embryonic Origins and Somatic Cells in Pig , 2013, PloS one.

[58]  M. Murakami,et al.  The Homeoprotein Nanog Is Required for Maintenance of Pluripotency in Mouse Epiblast and ES Cells , 2003, Cell.

[59]  B. Doble,et al.  The ground state of embryonic stem cell self-renewal , 2008, Nature.

[60]  Fabienne De Graeve,et al.  Leukemia Inhibitory Factor–dependent Transcriptional Activation in Embryonic Stem Cells , 1997, The Journal of cell biology.

[61]  Austin G Smith,et al.  Essential function of LIF receptor in motor neurons , 1995, Nature.

[62]  S. Wiese,et al.  Developmental Requirement of gp130 Signaling in Neuronal Survival and Astrocyte Differentiation , 1999, The Journal of Neuroscience.

[63]  J. Darnell,et al.  STAT signaling is active during early mammalian development , 1997, Developmental dynamics : an official publication of the American Association of Anatomists.

[64]  S. Akira,et al.  Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[65]  P. Heinrich,et al.  Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. , 1998, The Biochemical journal.

[66]  Janet Rossant,et al.  Direct Neural Fate Specification from Embryonic Stem Cells A Primitive Mammalian Neural Stem Cell Stage Acquired through a Default Mechanism , 2001, Neuron.

[67]  C. Lengner,et al.  Metastable pluripotent states in NOD-mouse-derived ESCs. , 2009, Cell stem cell.

[68]  D. Hilfiker-Kleiner,et al.  Survival pathways in hypertrophy and heart failure: The gp130-STAT3 axis , 2007, Basic Research in Cardiology.

[69]  B. Hogan,et al.  Derivation of Pluripotential Embryonic Stem Cells from Murine Primordial Germ Cells in Culture. , 1993 .

[70]  A. Smith,et al.  Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. , 1998, Genes & development.

[71]  Austin G Smith,et al.  FGF stimulation of the Erk1/2 signalling cascade triggers transition of pluripotent embryonic stem cells from self-renewal to lineage commitment , 2007, Development.

[72]  C. Lengner,et al.  Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs , 2010, Proceedings of the National Academy of Sciences.

[73]  Chad A. Cowan,et al.  The Src Family of Tyrosine Kinases Is Important for Embryonic Stem Cell Self-renewal* , 2004, Journal of Biological Chemistry.

[74]  J. Nichols,et al.  Functional Expression Cloning of Nanog, a Pluripotency Sustaining Factor in Embryonic Stem Cells , 2003, Cell.

[75]  A. Dierich,et al.  The Ribosomal S6 Kinases, cAMP-responsive Element-binding, and STAT3 Proteins Are Regulated by Different Leukemia Inhibitory Factor Signaling Pathways in Mouse Embryonic Stem Cells* , 2001, The Journal of Biological Chemistry.

[76]  M. Trotter,et al.  Derivation of pluripotent epiblast stem cells from mammalian embryos , 2007, Nature.

[77]  P. Zandstra,et al.  Spatial Organization of Embryonic Stem Cell Responsiveness to Autocrine Gp130 Ligands Reveals an Autoregulatory Stem Cell Niche , 2006, Stem cells.

[78]  Angelique M. Nelson,et al.  Derivation of naïve human embryonic stem cells , 2014, Proceedings of the National Academy of Sciences.

[79]  R. Young,et al.  Systematic Identification of Culture Conditions for Induction and Maintenance of Naive Human Pluripotency , 2014, Cell stem cell.

[80]  C. Ware,et al.  Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death. , 1995, Development.

[81]  Ying Gu,et al.  Steel factor controls primordial germ cell survival and motility from the time of their specification in the allantois, and provides a continuous niche throughout their migration , 2009, Development.

[82]  Ana D. Lopez,et al.  Activin A Maintains Pluripotency of Human Embryonic Stem Cells in the Absence of Feeder Layers , 2005, Stem cells.

[83]  L. C. Stevens Origin of testicular teratomas from primordial germ cells in mice. , 1967, Journal of the National Cancer Institute.

[84]  S. Weiss,et al.  The Ciliary Neurotrophic Factor/Leukemia Inhibitory Factor/gp130 Receptor Complex Operates in the Maintenance of Mammalian Forebrain Neural Stem Cells , 2001, The Journal of Neuroscience.

[85]  H. Ng,et al.  Induction of a human pluripotent state with distinct regulatory circuitry that resembles preimplantation epiblast. , 2013, Cell stem cell.

[86]  P. Zandstra,et al.  LIF‐mediated control of embryonic stem cell self‐renewal emerges due to an autoregulatory loop , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[87]  Warren S. Alexander,et al.  A family of cytokine-inducible inhibitors of signalling , 1997, Nature.

[88]  Stephen Brown,et al.  JAK/STAT signalling in Drosophila controls cell motility during germ cell migration , 2006, Developmental dynamics : an official publication of the American Association of Anatomists.

[89]  Hitoshi Niwa,et al.  A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells , 2009, Nature.

[90]  A. Cumano,et al.  Jak2 Deficiency Defines an EssentialDevelopmental Checkpoint in DefinitiveHematopoiesis , 1998, Cell.

[91]  Ana D. Lopez,et al.  Maintenance of Pluripotency in Human Embryonic Stem Cells Is STAT3 Independent , 2004, Stem cells.

[92]  F. Tang,et al.  Epigenetic reversion of post-implantation epiblast to pluripotent embryonic stem cells , 2009, Nature.

[93]  M. Azim Surani,et al.  Blimp1 is a critical determinant of the germ cell lineage in mice , 2005, Nature.

[94]  J. Nichols,et al.  Oct4 and LIF/Stat3 additively induce Krüppel factors to sustain embryonic stem cell self-renewal. , 2009, Cell stem cell.

[95]  R. McKay,et al.  New cell lines from mouse epiblast share defining features with human embryonic stem cells , 2007, Nature.

[96]  Holm Zaehres,et al.  LIF/STAT3 Signaling Fails to Maintain Self‐Renewal of Human Embryonic Stem Cells , 2004, Stem cells.

[97]  V. Poli,et al.  Essential Role of STAT3 in the Control of the Acute-Phase Response as Revealed by Inducible Gene Activation in the Liver , 2001, Molecular and Cellular Biology.

[98]  J. Nichols,et al.  Rebuilding Pluripotency from Primordial Germ Cells , 2013, Stem cell reports.

[99]  Paul Bertone,et al.  Identification of the missing pluripotency mediator downstream of leukaemia inhibitory factor , 2013, The EMBO journal.

[100]  J. Nichols,et al.  Physiological rationale for responsiveness of mouse embryonic stem cells to gp130 cytokines. , 2001, Development.

[101]  P. Heinrich,et al.  Principles of interleukin (IL)-6-type cytokine signalling and its regulation. , 2003, The Biochemical journal.