scholarly journals Regulation of embryonic stem cell self-renewal and pluripotency by leukaemia inhibitory factor

2011 ◽  
Vol 438 (1) ◽  
pp. 11-23 ◽  
Author(s):  
Hiroyuki Hirai ◽  
Peter Karian ◽  
Nobuaki Kikyo
Keyword(s):  
Stem Cells ◽  
Embryonic Stem ◽  
Gene Expression Pattern ◽  
Receptor Activation ◽  
Janus Kinase ◽  
Inhibitory Factor ◽  
Mitogen Activated Protein Kinase ◽  
Leukaemia Inhibitory Factor ◽  
Signalling Pathways ◽  
Self Renewal

LIF (leukaemia inhibitory factor) is a key cytokine for maintaining self-renewal and pluripotency of mESCs (mouse embryonic stem cells). Upon binding to the LIF receptor, LIF activates three major intracellular signalling pathways: the JAK (Janus kinase)/STAT3 (signal transducer and activator of transcription 3), PI3K (phosphoinositide 3-kinase)/AKT and SHP2 [SH2 (Src homology 2) domain-containing tyrosine phosphatase 2]/MAPK (mitogen-activated protein kinase) pathways. These pathways converge to orchestrate the gene expression pattern specific to mESCs. Among the many signalling events downstream of the LIF receptor, activation and DNA binding of the transcription factor STAT3 plays a central role in transducing LIF's functions. The fundamental role of LIF for pluripotency was highlighted further by the discovery that LIF accelerates the conversion of epiblast-derived stem cells into a more fully pluripotent state. In the present review, we provide an overview of the three major LIF signalling pathways, the molecules that interact with STAT3 and the current interpretations of the roles of LIF in pluripotency.

182. NOVEL SIGNALLING IN MOUSE EMBRYONIC STEM CELLS GENERATES PRIMITIVE ECTODERM-LIKE CELLS

2009 ◽  
Vol 21 (9) ◽  
pp. 100
Author(s):  
M. B. Morris ◽  
N. Hamra ◽  
A. C. Lonic ◽  
F. Felquer
Keyword(s):  
Es Cells ◽  
Embryonic Stem ◽  
Cell Types ◽  
Leukaemia Inhibitory Factor ◽  
Signalling Pathways ◽  
Specific Cell ◽  
Self Renewal ◽  
Mouse Es Cells ◽  
Homogeneous Production ◽  
Extracellular Molecules

The phenotypic status of embryonic stem (ES) cells is controlled in part by signalling pathways which translate inputs mediated by extracellular molecules. An important extracellular protagonist in mouse ES cells is LIF (leukaemia inhibitory factor) which interacts with the gp130–LIFR receptor complex to activate a number of downstream signalling pathways, including the STAT3, MEK/ERK and PI3K/Akt. These pathways, together with others, interact in complex and sometimes competing ways to generate the well-known characteristics of mouse ES cells of self-renewal, high rates of proliferation, and pluripotence. The addition of a second molecule, L-proline, to the extracellular environment alters the pluripotent status of mouse ES cells, converting them to a second pluripotent population equivalent to the primitive ectoderm of the pre-gastrulating embryo. This conversion, from ES cells to primitive ectoderm-like cells, primes the latter for directed differentiation to specific cell types (1). Here we show, using inhibitor studies and kinome array analysis, that this small molecule appears to work by (i) changing the balance in activity of signalling pathways already stimulated by LIF and (ii) activating additional signalling pathways. Specifically, L-proline rapidly further activates the LIF-stimulated MEK/ERK pathway, tipping the balance in favour of primitive-ectoderm formation and away from ES-cell self-renewal sustained by LIF-mediated activation of the STAT3 pathway. In addition, L-proline rapidly stimulates other pathways including p38, mTOR and PI3K/Akt each of which contributes, to a greater or lesser extent, to the conversion to primitive ectoderm-like cells. These results indicate that (i) L-proline acts in novel ways to stimulate embryo-like developmental progression in ES cells and (ii) through the addition of small, nontoxic activators and inhibitors of signalling pathways, the differentiation of pluripotent ES cells might be controlled sufficiently well for the homogeneous production of specific cell types suitable for use in animal models of human disease.

scholarly journals ZMYM2 inhibits NANOG-mediated reprogramming

2019 ◽  
Vol 4 ◽  
pp. 88 ◽  
Author(s):  
Moyra Lawrence ◽  
Thorold W. Theunissen ◽  
Patrick Lombard ◽  
David J. Adams ◽  
José C. R. Silva
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Somatic Cells ◽  
Embryonic Stem ◽  
The Self ◽  
Negative Regulator ◽  
Leukaemia Inhibitory Factor ◽  
Self Renewal ◽  
Epiblast Stem Cells

Background: NANOG is a homeodomain-containing transcription factor which forms one of the hubs in the pluripotency network and plays a key role in the reprogramming of somatic cells and epiblast stem cells to naïve pluripotency.  Studies have found that NANOG has many interacting partners and some of these were shown to play a role in its ability to mediate reprogramming. In this study, we set out to analyse the effect of NANOG interactors on the reprogramming process. Methods: Epiblast stem cells and somatic cells were reprogrammed to naïve pluripotency using MEK/ERK inhibitor PD0325901, GSK3β inhibitor CHIR99021 and Leukaemia Inhibitory Factor (together termed 2i Plus LIF). Zmym2 was knocked out using the CRISPR/Cas9 system or overexpressed using the PiggyBac system. Reprogramming was quantified after ZMYM2 deletion or overexpression, in diverse reprogramming systems. In addition, embryonic stem cell self renewal was quantified in differentiation assays after ZMYM2 removal or overexpression. Results: In this work, we identified ZMYM2/ZFP198, which physically associates with NANOG as a key negative regulator of NANOG-mediated reprogramming of both epiblast stem cells and somatic cells. In addition, ZMYM2 impairs the self renewal of embryonic stem cells and its overexpression promotes differentiation. Conclusions: We propose that ZMYM2 curtails NANOG’s actions during the reprogramming of both somatic cells and epiblast stem cells and impedes embryonic stem cell self renewal, promoting differentiation.

Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells

Nature ◽  
1988 ◽  
Vol 336 (6200) ◽  
pp. 684-687 ◽  
Author(s):  
R. Lindsay Williams ◽  
Douglas J. Hilton ◽  
Shirley Pease ◽  
Tracy A. Willson ◽  
Colin L. Stewart ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Myeloid Leukaemia ◽  
Embryonic Stem ◽  
Inhibitory Factor ◽  
Leukaemia Inhibitory Factor ◽  
Developmental Potential

scholarly journals Function of leukaemia inhibitory factor in spermatogenesis of a teleost fish, the medaka Oryzias latipes

Zygote ◽  
2019 ◽  
Vol 27 (6) ◽  
pp. 423-431 ◽  
Author(s):  
Ryuichi Satoh ◽  
Hisanori Bando ◽  
Noriyoshi Sakai ◽  
Tomoya Kotani ◽  
Masakane Yamashita
Keyword(s):  
Stem Cells ◽  
Primordial Germ Cells ◽  
Embryonic Stem ◽  
Inhibitory Factor ◽  
Leukaemia Inhibitory Factor ◽  
Hormonal Stimulation ◽  
A Cell ◽  
Established Cell

SummaryIn response to gonadotropins and androgens, testicular cells produce various molecules that control proper proliferation and differentiation of spermatogenic cells through their paracrine and autocrine actions. However, molecules functioning downstream of the hormonal stimulation are poorly understood. Leukaemia inhibitory factor (Lif) is known to maintain the pluripotency of stem cells including embryonic stem cells and primordial germ cells at least in vitro, but its actual roles in vivo remain to be elucidated. To clarify the function of Lif in teleost (medaka) testes, we examined the effects of Lif on spermatogenesis in a newly established cell culture system using a cell line (named Mtp1) derived from medaka testicular somatic cells as feeder cells. We found that addition of baculovirus-produced recombinant medaka Lif to the culture medium or co-culture with Lif-overexpressing Mtp1 cells increased the number of spermatogonia. In situ hybridization and immunohistochemical analyses of the medaka testes showed that mRNAs and proteins of Lif are expressed in spermatogonia and the surrounding Sertoli cells, with higher expression levels in type A (undifferentiated) spermatogonia than in type B (differentiated) spermatogonia. Our findings suggest that Lif regulates spermatogonial cell proliferation in the medaka.

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