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Leukemia inhibitory factor

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Template:PBB 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.[3]

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.

Pregnancy

Leukemia inhibitory factor is a cytokine expressed in the uterus during the secretory phase of the menstrual cycle, as well as expressed during a normal pregnancy.[4] Specifically, LIF is expressed in uterine endometrial glands and is under maternal control.[5] When the fertilized zygote has reached the blastocyst stage, the stromal cells surrounding the blastocyst produce leukemia inhibitory factor, which needed for the blastocyst to implant into the uterine endometrium.[4]

During pregnancy leukemia inhibitory growth factor is involved in decidualization of the maternal endometrium and implantation of the blastocyst to the endometrium.[4] LIF levels are highest on the fourth day of pregnancy indicating its involvement in implantation.[5]  Implantation is critical in pregnancy in order to establish the placenta and maternal-fetal interface. Fetal endothelial cells also express the receptor for leukemia inhibitory factor, indicating it may be involved in placental angiogenesis.[6] There is also evidence leukemia inhibitory factor is involved in the survival and proliferation of primordial germ cells, which are the cellular origins of spermatozoa and oocytes.[7]

Decreased secretion of leukemia inhibitory factor is associated with poor or no implantation and, thus, pregnancy loss.  Women with decreased production of LIF and other cytokines are fertile and able to become pregnant, but there is an increased risk for unexplained, recurrent miscarriages.[5][8]

Use in stem cell culture

Removal of LIF pushes stem cells toward differentiation, but they retain their proliferative potential or pluripotency. Therefore LIF is used in mouse embryonic stem cell culture. It is necessary to maintain the stem cells in an undifferentiated state, 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.[9][10]

References

  1. ^ Wenwei Hu, Zhaohui Feng, Angelika K. Teresky1, Arnold J. Levine (November 29, 2007). "p53 regulates maternal reproduction through LIF". Nature. 450 (7170): 721–724. doi:10.1038/nature05993. PMID 18046411.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: numeric names: authors list (link)
  2. ^ Aghajanova, L (2004). "Leukemia inhibitory factor and human embryo implantation". Annals of the New York Academy of Sciences. 1034 (1): 176–83. doi:10.1196/annals.1335.020. PMID 15731310.
  3. ^ Suman P, Malhotra SS, Gupta SK (Oct 2013). "LIF-STAT signaling and trophoblast biology". JAKSTAT. 2 (4): e25155. doi:10.4161/jkst.25155. PMID 24416645.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ a b c Norwitz, Errol R.; Schust, Danny J.; Fisher, Susan J. (2001-11-08). "Implantation and the Survival of Early Pregnancy". New England Journal of Medicine. 345 (19): 1400–1408. doi:10.1056/NEJMra000763. ISSN 0028-4793. PMID 11794174.
  5. ^ a b c Stewart, Colin L.; Kaspar, Petr; Brunet, Lisa J.; Bhatt, Harshida; Gadi, Inder; Köntgen, Frank; Abbondanzo, Susan J. (1992-09-03). "Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor". Nature. 359 (6390): 76–79. doi:10.1038/359076a0.
  6. ^ Sharkey, AM; King, A; Clark, DE; Burrows, TD; Jokhi, PP; Charnock-Jones, DS; Loke, YW; Smith, SK (February 1999). "9916002". Biol Reprod. doi:10.1095/​biolreprod60.2.355. PMID 9916002. {{cite journal}}: zero width space character in |doi= at position 9 (help)
  7. ^ Pesce, M; Farracee, MG; Piacentini, M; Dolci, S; De Felici, M (1993). "Stem cell factor and leukemia inhibitory factor promote primordial germ cell survival by suppressing programmed cell death (apoptosis)". Development. PMID 7505738.
  8. ^ Piccinni, Marie-Pierre; Beloni, Lucio; Livi, Claudia; Maggi, Enrico; Scarselli, Gianfranco; Romagnani, Sergio. "Defective production of both leukemia inhibitory factor and type 2 T-helper cytokines by decidual T cells in unexplained recurrent abortions". Nature Medicine. 4 (9): 1020–1024. doi:10.1038/2006.
  9. ^ Kawahara Y, Manabe T, Matsumoto M, Kajiume T, Matsumoto M, Yuge L (2009). Zwaka, Thomas (ed.). "LIF-Free Embryonic Stem Cell Culture in Simulated Microgravity". PLoS ONE. 4 (7): e6343. doi:10.1371/journal.pone.0006343. PMC 2710515. PMID 19626124.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  10. ^ "CGS : PTO Finds Stem Cell Patent Anticipated, Obvious in Light of 'Significant Guideposts'".
  • Author A. "Application of recombinant human leukemia inhibitory factor (LIF)for maintenance of mouse embryonic stem cells". Journal of Biotechnology. 172: 67–72. doi:10.1016/j.jbiotec.2013.12.012. {{cite journal}}: |author= has generic name (help)

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