Defining the role of oxygen tension in human neural progenitor fate

Yuan Xie; Jin Zhang; Ying Lin; Xavier Gaeta; Xiangzhi Meng; Dona R R Wisidagama; Jessica Cinkornpumin; Carla M Koehler; Cindy S Malone; Michael A Teitell; William E Lowry

doi:10.1016/j.stemcr.2014.09.021

Defining the role of oxygen tension in human neural progenitor fate

Stem Cell Reports. 2014 Nov 11;3(5):743-57. doi: 10.1016/j.stemcr.2014.09.021. Epub 2014 Oct 30.

Authors

Affiliations

¹ Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Department of Biology, California State University, Northridge, Northridge, CA 91330, USA.
⁵ Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁶ Eli and Edythe Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: [email protected].
⁷ Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: [email protected].

Abstract

Hypoxia augments human embryonic stem cell (hESC) self-renewal via hypoxia-inducible factor 2α-activated OCT4 transcription. Hypoxia also increases the efficiency of reprogramming differentiated cells to a pluripotent-like state. Combined, these findings suggest that low O2 tension would impair the purposeful differentiation of pluripotent stem cells. Here, we show that low O2 tension and hypoxia-inducible factor (HIF) activity instead promote appropriate hESC differentiation. Through gain- and loss-of-function studies, we implicate O2 tension as a modifier of a key cell fate decision, namely whether neural progenitors differentiate toward neurons or glia. Furthermore, our data show that even transient changes in O2 concentration can affect cell fate through HIF by regulating the activity of MYC, a regulator of LIN28/let-7 that is critical for fate decisions in the neural lineage. We also identify key small molecules that can take advantage of this pathway to quickly and efficiently promote the development of mature cell types.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aryl Hydrocarbon Receptor Nuclear Translocator / genetics
Aryl Hydrocarbon Receptor Nuclear Translocator / metabolism
Basic Helix-Loop-Helix Transcription Factors / genetics
Basic Helix-Loop-Helix Transcription Factors / metabolism
Cell Differentiation / drug effects*
Cell Differentiation / genetics
Cell Hypoxia
Cell Line
Cell Proliferation / drug effects*
Cell Proliferation / genetics
Cells, Cultured
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
MicroRNAs / genetics
MicroRNAs / metabolism
Neural Stem Cells / cytology
Neural Stem Cells / drug effects*
Neural Stem Cells / metabolism
Neurogenesis / drug effects
Neurogenesis / genetics
Oligonucleotide Array Sequence Analysis
Oxygen / metabolism
Oxygen / pharmacology*
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
RNA Interference
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism
Signal Transduction / drug effects
Signal Transduction / genetics
Transcriptome / drug effects
Transcriptome / genetics

Substances

Basic Helix-Loop-Helix Transcription Factors
Hypoxia-Inducible Factor 1, alpha Subunit
LIN28B protein, human
MYC protein, human
MicroRNAs
Proto-Oncogene Proteins c-myc
RNA-Binding Proteins
mirnlet7 microRNA, human
Aryl Hydrocarbon Receptor Nuclear Translocator
endothelial PAS domain-containing protein 1
Oxygen

Associated data

GEO/GSE61842

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding