New insights into the mechanisms of embryonic stem cell self-renewal under hypoxia: a multifactorial analysis approach.
Previous reports have shown that culturing mouse embryonic stem (mES) cells at different oxygen tensions originated different cell proliferation patterns and commitment stages depending on which signaling pathways are activated or inhibited to support the pluripotency state. Herein we provide new insights into the mechanisms by which oxygen is influencing mES cell self-renewal and pluripotency. A multifactorial approach was developed to rationally evaluate the singular and interactive control of MEK/ERK pathway, GSK-3 inhibition, and LIF/STAT3 signaling at physiological and non-physiological oxygen tensions. Collectively, our methodology revealed a significant role of GSK-3-mediated signaling towards maintenance of mES cell pluripotency at lower O(2) tensions. Given the central role of this signaling pathway, future studies will need to focus on the downstream mechanisms involved in ES cell self-renewal under such conditions, and ultimately how these findings impact human models of pluripotency.
Department of Bioengineering, Centre for Biological and Chemical Engineering, Instituto Superior Técnico, Technical University of Lisbon, Lisboa, Portugal.
Hélder S C
HS
Barbosa
Tiago G
TG
Fernandes
Tiago P
TP
Dias
Maria Margarida
MM
Diogo
Joaquim M S
JM
Cabral
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D049109:Cell Proliferation; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D053595:Embryonic Stem Cells / Q000201:enzymology / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051519:Fibroblast Growth Factor 4 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000860:Hypoxia / Q000503:physiopathology*; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000201:enzymology / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells
D001549:Benzamides; C473711:Chir 99021; C496446:Fgf4 protein, mouse; D051519:Fibroblast Growth Factor 4; D053605:Leukemia Inhibitory Factor; D011725:Pyridines; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C506614:mirdametinib; D004159:Diphenylamine; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D010100:Oxygen