Derivation of trophoblast stem cells from naïve human pluripotent stem cells
- Washington University School of Medicine, United States
Abstract
Naïve human pluripotent stem cells (hPSCs) provide a unique experimental platform of cell fate decisions during pre-implantation development, but their lineage potential remains incompletely characterized. As naïve hPSCs share transcriptional and epigenomic signatures with trophoblast cells, it has been proposed that the naïve state may have enhanced predisposition for differentiation along this extraembryonic lineage. Here we examined the trophoblast potential of isogenic naïve and primed hPSCs. We found that naïve hPSCs can directly give rise to human trophoblast stem cells (hTSCs) and undergo further differentiation into both extravillous and syncytiotrophoblast. In contrast, primed hPSCs do not support hTSC derivation, but give rise to non-self-renewing cytotrophoblasts in response to BMP4. Global transcriptome and chromatin accessibility analyses indicate that hTSCs derived from naïve hPSCs are similar to blastocyst-derived hTSCs and acquire features of post-implantation trophectoderm. The derivation of hTSCs from naïve hPSCs will enable elucidation of early mechanisms that govern normal human trophoblast development and associated pathologies.
Data availability
The accession number for the RNA-seq and ATAC-seq data is GSE138762.
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Derivation of trophoblast stem cells from naïve human pluripotent stem cellsNCBI Gene Expression Omnibus, GSE138762.
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Reconstituting the transcriptome and DNA methylome landscapes of human implantationNCBI Gene Expression Omnibus, GSE109555.
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TFAP2C regulates transcription in human naive pluripotency by opening enhancersNCBI Gene Expression Omnibus, GSE101074.
Article and author information
Author details
Ramakrishna Kommagani
Thorold W Theunissen
Funding
Children's Discovery Institute (CDI-LI-2019-819)
- Lilianna Solnica-Krezel
- Thorold W Theunissen
McDonnell Center for Cellular and Molecular Neurobiology (22-3930-26275D)
- Thorold W Theunissen
NIH Director's New Innovator Award (DP2 GM137418)
- Thorold W Theunissen
Shipley Foundation Program for Innovation in Stem Cell Science
- Thorold W Theunissen
Edward Mallinckrodt Jr Foundation
- Thorold W Theunissen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Marianne E Bronner, California Institute of Technology, United States
Version history
- Received: October 6, 2019
- Accepted: February 11, 2020
- Accepted Manuscript published: February 12, 2020 (version 1)
- Version of Record published: March 9, 2020 (version 2)
Copyright
© 2020, Dong et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Derivation of trophoblast stem cells from naïve human pluripotent stem cells
eLife 9:e52504.
https://doi.org/10.7554/eLife.52504
Further reading
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Neural stem cells (NSCs) are multipotent and correct fate determination is crucial to guarantee brain formation and homeostasis. How NSCs are instructed to generate neuronal or glial progeny is not well understood. Here we addressed how murine adult hippocampal NSC fate is regulated and describe how Scaffold Attachment Factor B (SAFB) blocks oligodendrocyte production to enable neuron generation. We found that SAFB prevents NSC expression of the transcription factor Nuclear Factor I/B (NFIB) by binding to sequences in the Nfib mRNA and enhancing Drosha-dependent cleavage of the transcripts. We show that increasing SAFB expression prevents oligodendrocyte production by multipotent adult NSCs, and conditional deletion of Safb increases NFIB expression and oligodendrocyte formation in the adult hippocampus. Our results provide novel insights into a mechanism that controls Drosha functions for selective regulation of NSC fate by modulating the post-transcriptional destabilization of Nfib mRNA in a lineage-specific manner.
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