Leukemia inhibitory factor explained

Leukemia inhibitory factor, or LIF, is an interleukin 6 class cytokine that affects cell growth by inhibiting differentiation. When LIF levels drop, the cells differentiate.

Function

LIF derives its name from its ability to induce the terminal differentiation of myeloid leukemic cells, thus preventing their continued growth. Other properties attributed to the cytokine include: the growth promotion and cell differentiation of different types of target cells, influence on bone metabolism, cachexia, neural development, embryogenesis and inflammation. p53 regulated LIF has been shown to facilitate implantation in the mouse model and possibly in humans.^[1] It has been suggested that recombinant human LIF might help to improve the implantation rate in women with unexplained infertility.^[2]

Binding/activation

LIF binds to the specific LIF receptor (LIFR-α) which forms a heterodimer with a specific subunit common to all members of that family of receptors, the GP130 signal transducing subunit. This leads to activation of the JAK/STAT (Janus kinase/signal transducer and activator of transcription) and MAPK (mitogen activated protein kinase) cascades.

Expression

LIF is normally expressed in the trophectoderm of the developing embryo, with its receptor LIFR expressed throughout the inner cell mass. As embryonic stem cells are derived from the inner cell mass at the blastocyst stage, removing them from the inner cell mass also removes their source of LIF. Recombinant LIF has been produced in plants by InVitria.

Use in stem cell culture

LIF is often added to stem cell culture media as an alternative to feeder cell culture, due to the limitation that feeder cells present by only producing LIF on their cell surfaces. Feeder cells lacking the LIF gene do not effectively support stem cells.^[3] LIF promotes self-renewal by recruiting signal transducer and activator of transcription 3 (Stat3). Stat3 is recruited to the activated LIF receptor and phosphorylated by Janus kinase. It bears noting that LIF and Stat3 are not sufficient to inhibit stem cell differentiation, as cells will differentiate upon removal of serum. During the reversibility phase of differentiation from naive pluripotency, it is possible to revert cells back to naive pluripotency through the addition of LIF.^[4] Removal of LIF pushes stem cells toward differentiation, however genetic manipulation of embryonic stem cells allows for LIF independent growth, notably overexpression of the gene Nanog.

LIF is typically added to stem cell culture medium to reduce spontaneous differentiation.^{[5] [6]}

Further reading

• Patterson PH . Leukemia inhibitory factor, a cytokine at the interface between neurobiology and immunology . Proceedings of the National Academy of Sciences of the United States of America . 91 . 17 . 7833–5 . August 1994 . 8058719 . 44497 . 10.1073/pnas.91.17.7833 . 1994PNAS...91.7833P . free .
• Aghajanova L . Leukemia inhibitory factor and human embryo implantation . Annals of the New York Academy of Sciences . 1034 . 176–83 . December 2004 . 1 . 15731310 . 10.1196/annals.1335.020 . 2004NYASA1034..176A . 22083037 .
• Králícková M, Síma P, Rokyta Z . Role of the leukemia-inhibitory factor gene mutations in infertile women: the embryo-endometrial cytokine cross talk during implantation--a delicate homeostatic equilibrium . Folia Microbiologica . 50 . 3 . 179–86 . 2005 . 16295654 . 10.1007/BF02931563 . 22515632 .
• Stahl J, Gearing DP, Willson TA, Brown MA, King JA, Gough NM . Structural organization of the genes for murine and human leukemia inhibitory factor. Evolutionary conservation of coding and non-coding regions . The Journal of Biological Chemistry . 265 . 15 . 8833–41 . May 1990 . 10.1016/S0021-9258(19)38963-X . 1692837 . free .
• Bazan JF . Neuropoietic cytokines in the hematopoietic fold . Neuron . 7 . 2 . 197–208 . August 1991 . 1714745 . 10.1016/0896-6273(91)90258-2 . 24161982 .
• Lowe DG, Nunes W, Bombara M, McCabe S, Ranges GE, Henzel W, Tomida M, Yamamoto-Yamaguchi Y, Hozumi M, Goeddel DV . Genomic cloning and heterologous expression of human differentiation-stimulating factor . DNA . 8 . 5 . 351–9 . June 1989 . 2475312 . 10.1089/dna.1.1989.8.351 .
• Sutherland GR, Baker E, Hyland VJ, Callen DF, Stahl J, Gough NM . Grant Robert Sutherland . The gene for human leukemia inhibitory factor (LIF) maps to 22q12 . Leukemia . 3 . 1 . 9–13 . January 1989 . 2491897 .
• Mori M, Yamaguchi K, Abe K . Purification of a lipoprotein lipase-inhibiting protein produced by a melanoma cell line associated with cancer cachexia . Biochemical and Biophysical Research Communications . 160 . 3 . 1085–92 . May 1989 . 2730639 . 10.1016/S0006-291X(89)80114-7 .
• Gough NM, Gearing DP, King JA, Willson TA, Hilton DJ, Nicola NA, Metcalf D . Molecular cloning and expression of the human homologue of the murine gene encoding myeloid leukemia-inhibitory factor . Proceedings of the National Academy of Sciences of the United States of America . 85 . 8 . 2623–7 . April 1988 . 3128791 . 280050 . 10.1073/pnas.85.8.2623 . 1988PNAS...85.2623G . free .
• Williams RL, Hilton DJ, Pease S, Willson TA, Stewart CL, Gearing DP, Wagner EF, Metcalf D, Nicola NA, Gough NM . Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells . Nature . 336 . 6200 . 684–7 . December 1988 . 3143916 . 10.1038/336684a0 . 1988Natur.336..684W . 4346252 .
• Moreau JF, Donaldson DD, Bennett F, Witek-Giannotti J, Clark SC, Wong GG . Leukaemia inhibitory factor is identical to the myeloid growth factor human interleukin for DA cells . Nature . 336 . 6200 . 690–2 . December 1988 . 3143918 . 10.1038/336690a0 . 1988Natur.336..690M . 4259150 .
• Yamaguchi M, Miki N, Ono M, Ohtsuka C, Demura H, Kurachi H, Inoue M, Endo H, Taga T, Kishimoto T . Inhibition of growth hormone-releasing factor production in mouse placenta by cytokines using gp130 as a signal transducer . Endocrinology . 136 . 3 . 1072–8 . March 1995 . 7867561 . 10.1210/endo.136.3.7867561 .
• Schmelzer CH, Harris RJ, Butler D, Yedinak CM, Wagner KL, Burton LE . Glycosylation pattern and disulfide assignments of recombinant human differentiation-stimulating factor . Archives of Biochemistry and Biophysics . 302 . 2 . 484–9 . May 1993 . 8489250 . 10.1006/abbi.1993.1243 .
• Aikawa J, Ikeda-Naiki S, Ohgane J, Min KS, Imamura T, Sasai K, Shiota K, Ogawa T . Molecular cloning of rat leukemia inhibitory factor receptor alpha-chain gene and its expression during pregnancy . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1353 . 3 . 266–76 . September 1997 . 9349722 . 10.1016/s0167-4781(97)00079-1 .
• Hinds MG, Maurer T, Zhang JG, Nicola NA, Norton RS . Solution structure of leukemia inhibitory factor . The Journal of Biological Chemistry . 273 . 22 . 13738–45 . May 1998 . 9593715 . 10.1074/jbc.273.22.13738 . free .
• Toward a complete human genome sequence . Genome Research . 8 . 11 . 1097–108 . November 1998 . 9847074 . 10.1101/gr.8.11.1097 . ((Sanger Centre)), ((Washington University Genome Sequencing Center)) . free .
• Tanaka M, Hara T, Copeland NG, Gilbert DJ, Jenkins NA, Miyajima A . Reconstitution of the functional mouse oncostatin M (OSM) receptor: molecular cloning of the mouse OSM receptor beta subunit . Blood . 93 . 3 . 804–15 . February 1999 . 9920829 . 10.1182/blood.V93.3.804. 39078004 .
• Nakashima K, Yanagisawa M, Arakawa H, Kimura N, Hisatsune T, Kawabata M, Miyazono K, Taga T . Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300 . Science . 284 . 5413 . 479–82 . April 1999 . 10205054 . 10.1126/science.284.5413.479 . 1999Sci...284..479N .
• Dunham I, Shimizu N, Roe BA, Chissoe S, Hunt AR, Collins JE, Bruskiewich R, Beare DM, Clamp M, Smink LJ, Ainscough R, Almeida JP, Babbage A, Bagguley C, Bailey J, Barlow K, Bates KN, Beasley O, Bird CP, Blakey S, Bridgeman AM, Buck D, Burgess J, Burrill WD, O'Brien KP . The DNA sequence of human chromosome 22 . Nature . 402 . 6761 . 489–95 . December 1999 . 10591208 . 10.1038/990031 . 1999Natur.402..489D . free .

External links

• • Source of Recombiant Leukemia Inhibitory Factor (http://www.invitria.com/cell-culture-products-services/leukemia-inhibitory-factor-culture-media.html)

Notes and References

1. Hu W, Feng Z, Teresky AK, Levine AJ . p53 regulates maternal reproduction through LIF . Nature . 450 . 7170 . 721–4 . November 2007 . 18046411 . 10.1038/nature05993 . 2007Natur.450..721H . 4357527 .
2. Aghajanova L . Leukemia inhibitory factor and human embryo implantation . Annals of the New York Academy of Sciences . 1034 . 1 . 176–83 . December 2004 . 15731310 . 10.1196/annals.1335.020 . 2004NYASA1034..176A . 22083037 .
3. Stewart CL, Kaspar P, Brunet LJ, Bhatt H, Gadi I, Köntgen F, Abbondanzo SJ . Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor . Nature . 359 . 6390 . 76–9 . September 1992 . 1522892 . 10.1038/359076a0 . 1992Natur.359...76S . 4319278 .
4. Martello G, Smith A . The nature of embryonic stem cells . Annual Review of Cell and Developmental Biology . 30 . 647–75 . 2014 . 25288119 . 10.1146/annurev-cellbio-100913-013116 . free .
5. Kawahara Y, Manabe T, Matsumoto M, Kajiume T, Matsumoto M, Yuge L . LIF-free embryonic stem cell culture in simulated microgravity . PLOS ONE . 4 . 7 . e6343 . July 2009 . 19626124 . 2710515 . 10.1371/journal.pone.0006343 . Zwaka T . 2009PLoSO...4.6343K . free .
6. Web site: CGS : PTO Finds Stem Cell Patent Anticipated, Obvious in Light of 'Significant Guideposts' . https://web.archive.org/web/20111004055228/http://www.geneticsandsociety.org/article.php?id=5197 . 2011-10-04 . dead .