Unique molecular events during reprogramming of human somatic cells to induced pluripotent stem cells (iPSCs) at naïve state
- Tongji University, China
Abstract
Derivation of human naïve cells in the ground state of pluripotency provides promising avenues for developmental biology studies and therapeutic manipulations. However, the molecular mechanisms involved in the establishment and maintenance of human naïve pluripotency remain poorly understood. Using the human inducible reprogramming system together with the 5iLAF naïve induction strategy, integrative analysis of transcriptional and epigenetic dynamics across the transition from human fibroblasts to naïve iPSCs revealed ordered waves of gene network activation sharing signatures with those found during embryonic development from late embryogenesis to pre-implantation stages. More importantly, Transcriptional analysis showed a significant transient reactivation of transcripts with 8-cell-stage-like characteristics in the late stage of reprogramming, suggesting transient activation of gene network with human zygotic genome activation (ZGA)-like signatures during the establishment of naïve pluripotency. Together, Dissecting the naïve reprogramming dynamics by integrative analysis improves the understanding of the molecular features involved in the generation of naïve pluripotency directly from somatic cells.
Data availability
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Integrative analysis of reprogramming human fibroblast cells to naïve pluripotencyPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE89072).
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Integrative analyses of human reprogramming reveal dynamic nature of induced pluripotencyPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE62777).
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Tracing pluripotency of human early embryos and embryonic stem cells by single cell RNA-seqPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE36552).
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The DNA methylation landscape of human early embryosPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE49828).
Article and author information
Author details
Funding
National Natural Science Foundation of China (31671530)
- Shaorong Gao
Ministry of Science and Technology of the People's Republic of China (2016YFA0100400)
- Shaorong Gao
National Natural Science Foundation of China (31325019)
- Shaorong Gao
National Natural Science Foundation of China (31471392)
- Shaorong Gao
Ministry of Science and Technology of the People's Republic of China (2014CB964601)
- Shaorong Gao
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Human subjects: Human skin specimens from abortive fetus were obtained from the Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Tongji University to make human embryonic fibroblasts (HEFs). The patients provided informed consent for tissue donations, and the Biological Research Ethics Committee of Tongji University approved the study.
Copyright
© 2018, Wang 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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Unique molecular events during reprogramming of human somatic cells to induced pluripotent stem cells (iPSCs) at naïve state
eLife 7:e29518.
https://doi.org/10.7554/eLife.29518
Further reading
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Amniogenesis, a process critical for continuation of healthy pregnancy, is triggered in a collection of pluripotent epiblast cells as the human embryo implants. Previous studies have established that bone morphogenetic protein (BMP) signaling is a major driver of this lineage specifying process, but the downstream BMP-dependent transcriptional networks that lead to successful amniogenesis remain to be identified. This is, in part, due to the current lack of a robust and reproducible model system that enables mechanistic investigations exclusively into amniogenesis. Here, we developed an improved model of early amnion specification, using a human pluripotent stem cell-based platform in which the activation of BMP signaling is controlled and synchronous. Uniform amniogenesis is seen within 48 hr after BMP activation, and the resulting cells share transcriptomic characteristics with amnion cells of a gastrulating human embryo. Using detailed time-course transcriptomic analyses, we established a previously uncharacterized BMP-dependent amniotic transcriptional cascade, and identified markers that represent five distinct stages of amnion fate specification; the expression of selected markers was validated in early post-implantation macaque embryos. Moreover, a cohort of factors that could potentially control specific stages of amniogenesis was identified, including the transcription factor TFAP2A. Functionally, we determined that, once amniogenesis is triggered by the BMP pathway, TFAP2A controls the progression of amniogenesis. This work presents a temporally resolved transcriptomic resource for several previously uncharacterized amniogenesis states and demonstrates a critical intermediate role for TFAP2A during amnion fate specification.
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