LIF supports primitive endoderm expansion during pre-implantation development
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LIF supports primitive endoderm expansion during pre-implantation development. / Morgani, Sophie M; Brickman, Joshua M.
In: Development (Cambridge, England), Vol. 142, No. 20, 15.10.2015, p. 3488-99.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - LIF supports primitive endoderm expansion during pre-implantation development
AU - Morgani, Sophie M
AU - Brickman, Joshua M
N1 - © 2015. Published by The Company of Biologists Ltd.
PY - 2015/10/15
Y1 - 2015/10/15
N2 - Embryonic stem cells (ESCs) are pluripotent cell lines that can be maintained indefinitely in an early developmental state. ESC culture conditions almost always require the cytokine LIF to maintain self-renewal. As ESCs are not homogeneous but contain multiple populations reminiscent of the blastocyst, identifying the target cells of LIF is necessary to understand the propagation of pluripotency. We recently found that LIF acts under self-renewing conditions to stimulate the fraction of ESCs that express extraembryonic markers, but has little impact on pluripotent gene expression. Here, we report that LIF has two distinct roles: it blocks early epiblast (Epi) differentiation, and it supports the expansion of primitive endoderm (PrE)-primed ESCs and PrE in vivo. We find that activation of JAK/STAT signalling downstream of LIF occurs initially throughout the pre-implantation embryo, but later marks the PrE. Moreover, the addition of LIF to cultured embryos increases the GATA6(+) PrE population, whereas inhibition of JAK/STAT signalling reduces both NANOG(+) epiblast and GATA6(+) PrE. The reduction of the NANOG(+) Epi might be explained by its precocious differentiation to later Epi derivatives, whereas the increase in PrE is mediated both by an increase in proliferation and inhibition of PrE apoptosis that is normally triggered in embryos with an excess of GATA6(+) cells. Thus, it appears that the relative size of the PrE is determined by the number of LIF-producing cells in the embryo. This suggests a mechanism by which the embryo adjusts the relative ratio of the primary lineages in response to experimental manipulation.
AB - Embryonic stem cells (ESCs) are pluripotent cell lines that can be maintained indefinitely in an early developmental state. ESC culture conditions almost always require the cytokine LIF to maintain self-renewal. As ESCs are not homogeneous but contain multiple populations reminiscent of the blastocyst, identifying the target cells of LIF is necessary to understand the propagation of pluripotency. We recently found that LIF acts under self-renewing conditions to stimulate the fraction of ESCs that express extraembryonic markers, but has little impact on pluripotent gene expression. Here, we report that LIF has two distinct roles: it blocks early epiblast (Epi) differentiation, and it supports the expansion of primitive endoderm (PrE)-primed ESCs and PrE in vivo. We find that activation of JAK/STAT signalling downstream of LIF occurs initially throughout the pre-implantation embryo, but later marks the PrE. Moreover, the addition of LIF to cultured embryos increases the GATA6(+) PrE population, whereas inhibition of JAK/STAT signalling reduces both NANOG(+) epiblast and GATA6(+) PrE. The reduction of the NANOG(+) Epi might be explained by its precocious differentiation to later Epi derivatives, whereas the increase in PrE is mediated both by an increase in proliferation and inhibition of PrE apoptosis that is normally triggered in embryos with an excess of GATA6(+) cells. Thus, it appears that the relative size of the PrE is determined by the number of LIF-producing cells in the embryo. This suggests a mechanism by which the embryo adjusts the relative ratio of the primary lineages in response to experimental manipulation.
KW - Animals
KW - Apoptosis
KW - Blastocyst
KW - Cell Differentiation
KW - Cell Lineage
KW - Cytokines
KW - Embryonic Development
KW - Embryonic Stem Cells
KW - Endoderm
KW - Female
KW - Flow Cytometry
KW - GATA6 Transcription Factor
KW - Gene Expression Profiling
KW - Gene Expression Regulation, Developmental
KW - Interleukin-6
KW - Janus Kinases
KW - Leukemia Inhibitory Factor
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Microscopy, Confocal
KW - Phenotype
KW - Pluripotent Stem Cells
KW - STAT3 Transcription Factor
KW - Time Factors
U2 - 10.1242/dev.125021
DO - 10.1242/dev.125021
M3 - Journal article
C2 - 26395492
VL - 142
SP - 3488
EP - 3499
JO - Development
JF - Development
SN - 0950-1991
IS - 20
ER -
ID: 160407018