TY - JOUR
T1 - Hypoxia-inducible factors have distinct and stage-specific roles during reprogramming of human cells to pluripotency
AU - Mathieu, Julie
AU - Zhou, Wenyu
AU - Xing, Yalan
AU - Sperber, Henrik
AU - Ferreccio, Amy
AU - Agoston, Zsuzsa
AU - Kuppusamy, Kavitha T.
AU - Moon, Randall T.
AU - Ruohola-Baker, Hannele
N1 - Funding Information:
We thank Drs. Ware, Hockenbery, and Horwitz and members of the H.R.-B. laboratory for helpful discussions throughout this work. We thank Dr. Stadler for work early in the project. We thank Michael Choi and Timothy Dosey for technical help. We thank Pamela Troisch from Institute for Systems Biology for the microarray gene expression service and Dr. Mecham from Sage Bionetworks for some of the statistical analysis on microarray data. We thank Dr. Gardner for providing the scramble shRNA and shRNA against HIF1α. We also thank members of Tom & Sue Ellison Stem Cell Core for help on iPSC reprogramming procedures and cell cultures. This work was supported by fellowships from the American Heart Association (to J.M., W.Z., and Y.X.), a Tietze Award (to K.T.K.), and grants from the National Institutes of Health (R01GM097372, R01GM083867, and R01GM083867-02S2 to H.R.-B., U01HL100395 to Z.A. and R.T.M., and P01GM081619 to R.T.M. and H.R.-B.).
PY - 2014/5/1
Y1 - 2014/5/1
N2 - Pluripotent stem cells have distinct metabolic requirements, and reprogramming cells to pluripotency requires a shift from oxidative to glycolytic metabolism. Here, we show that this shift occurs early during reprogramming of human cells and requires hypoxia-inducible factors (HIFs) in a stage-specific manner. HIF1α and HIF2α are both necessary to initiate this metabolic switch and for the acquisition of pluripotency, and the stabilization of either protein during early phases of reprogramming is sufficient to induce the switch to glycolytic metabolism. In contrast, stabilization of HIF2α during later stages represses reprogramming, partly because of the upregulation of TNF-related apoptosis-inducing ligand (TRAIL). TRAIL inhibits induced pluripotent stem cell (iPSC) generation by repressing apoptotic caspase 3 activity specifically in cells undergoing reprogramming but not human embryonic stem cells (hESCs), and inhibiting TRAIL activity enhances human iPSC generation. These results shed light on the mechanisms underlying the metabolic shifts associated with the acquisition of a pluripotent identity during reprogramming.
AB - Pluripotent stem cells have distinct metabolic requirements, and reprogramming cells to pluripotency requires a shift from oxidative to glycolytic metabolism. Here, we show that this shift occurs early during reprogramming of human cells and requires hypoxia-inducible factors (HIFs) in a stage-specific manner. HIF1α and HIF2α are both necessary to initiate this metabolic switch and for the acquisition of pluripotency, and the stabilization of either protein during early phases of reprogramming is sufficient to induce the switch to glycolytic metabolism. In contrast, stabilization of HIF2α during later stages represses reprogramming, partly because of the upregulation of TNF-related apoptosis-inducing ligand (TRAIL). TRAIL inhibits induced pluripotent stem cell (iPSC) generation by repressing apoptotic caspase 3 activity specifically in cells undergoing reprogramming but not human embryonic stem cells (hESCs), and inhibiting TRAIL activity enhances human iPSC generation. These results shed light on the mechanisms underlying the metabolic shifts associated with the acquisition of a pluripotent identity during reprogramming.
UR - https://www.scopus.com/pages/publications/84899919010
U2 - 10.1016/j.stem.2014.02.012
DO - 10.1016/j.stem.2014.02.012
M3 - Article
C2 - 24656769
AN - SCOPUS:84899919010
SN - 1934-5909
VL - 14
SP - 592
EP - 605
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 5
ER -