Leukemia inhibitory factor

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LIF
LIF Crystal Structure.rsh.png
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesLIF, CDF, DIA, HILDA, MLPLI, leukemia inhibitory factor, interleukin 6 family cytokine, LIF interleukin 6 family cytokine
External IDsOMIM: 159540 MGI: 96787 HomoloGene: 1734 GeneCards: LIF
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001257135
NM_002309

NM_001039537
NM_008501

RefSeq (protein)

NP_001244064
NP_002300

NP_001034626
NP_032527

Location (UCSC)Chr 22: 30.24 – 30.25 MbChr 11: 4.21 – 4.22 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5] It has been suggested that recombinant human LIF might help to improve the implantation rate in women with unexplained infertility.[6]

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.[citation needed]

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.[7] 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.[8] 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.[9][10]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000128342 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000034394 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Hu W, Feng Z, Teresky AK, Levine AJ (November 2007). "p53 regulates maternal reproduction through LIF". Nature. 450 (7170): 721–4. Bibcode:2007Natur.450..721H. doi:10.1038/nature05993. PMID 18046411. S2CID 4357527.
  6. ^ Aghajanova L (December 2004). "Leukemia inhibitory factor and human embryo implantation". Annals of the New York Academy of Sciences. 1034 (1): 176–83. Bibcode:2004NYASA1034..176A. doi:10.1196/annals.1335.020. PMID 15731310. S2CID 22083037.
  7. ^ Stewart CL, Kaspar P, Brunet LJ, Bhatt H, Gadi I, Köntgen F, Abbondanzo SJ (September 1992). "Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor". Nature. 359 (6390): 76–9. Bibcode:1992Natur.359...76S. doi:10.1038/359076a0. PMID 1522892. S2CID 4319278.
  8. ^ Martello G, Smith A (2014). "The nature of embryonic stem cells". Annual Review of Cell and Developmental Biology. 30: 647–75. doi:10.1146/annurev-cellbio-100913-013116. PMID 25288119.
  9. ^ Kawahara Y, Manabe T, Matsumoto M, Kajiume T, Matsumoto M, Yuge L (July 2009). Zwaka T (ed.). "LIF-free embryonic stem cell culture in simulated microgravity". PLOS ONE. 4 (7): e6343. Bibcode:2009PLoSO...4.6343K. doi:10.1371/journal.pone.0006343. PMC 2710515. PMID 19626124.
  10. ^ "CGS : PTO Finds Stem Cell Patent Anticipated, Obvious in Light of 'Significant Guideposts'". Archived from the original on 2011-10-04.

Further reading

External links