HIF-2α suppresses p53 to enhance the stemness and regenerative potential of human embryonic stem cells.
Human embryonic stem cells (hESCs) have been reported to exert cytoprotective activity in the area of tissue injury. However, hypoxia/oxidative stress prevailing in the area of injury could activate p53, leading to death and differentiation of hESCs. Here we report that when exposed to hypoxia/oxidative stress, a small fraction of hESCs, namely the SSEA3+/ABCG2+ fraction undergoes a transient state of reprogramming to a low p53 and high hypoxia inducible factor (HIF)-2α state of transcriptional activity. This state can be sustained for a period of 2 weeks and is associated with enhanced transcriptional activity of Oct-4 and Nanog, concomitant with high teratomagenic potential. Conditioned medium obtained from the post-hypoxia SSEA3+/ABCG2+ hESCs showed cytoprotection both in vitro and in vivo. We termed this phenotype as the "enhanced stemness" state. We then demonstrated that the underlying molecular mechanism of this transient phenotype of enhanced stemness involved high Bcl-2, fibroblast growth factor (FGF)-2, and MDM2 expression and an altered state of the p53/MDM2 oscillation system. Specific silencing of HIF-2α and p53 resisted the reprogramming of SSEA3+/ABCG2+ to the enhanced stemness phenotype. Thus, our studies have uncovered a unique transient reprogramming activity in hESCs, the enhanced stemness reprogramming where a highly cytoprotective and undifferentiated state is achieved by transiently suppressing p53 activity. We suggest that this transient reprogramming is a form of stem cell altruism that benefits the surrounding tissues during the process of tissue regeneration.
Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. bikuldas@stanford.edu
Bikul
B
Das
Reza
R
Bayat-Mokhtari
Micky
M
Tsui
Shamim
S
Lotfi
Rika
R
Tsuchida
Dean W
DW
Felsher
Herman
H
Yeger
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018384:Oxidative Stress / Q000502:physiology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D000099162:Endothelial PAS Domain-Containing Protein 1; C495901:TP53 protein, human