1. Stem Cells and Regenerative Medicine

Unique molecular events during reprogramming of human somatic cells to induced pluripotent stem cells (iPSCs) at naïve state

  1. Yixuan Wang  Is a corresponding author
  2. Chengchen Zhao
  3. Zhenzhen Hou
  4. Yuanyuan Yang
  5. Yan Bi
  6. Hong Wang
  7. Yong Zhang
  8. Shaorong Gao  Is a corresponding author
  1. Tongji University, China
https://doi.org/10.7554/eLife.29518
Share this article
Cite this article
  1. Yixuan Wang
  2. Chengchen Zhao
  3. Zhenzhen Hou
  4. Yuanyuan Yang
  5. Yan Bi
  6. Hong Wang
  7. Yong Zhang
  8. Shaorong Gao
(2018)
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
  2. Download BibTeX
  3. Download .RIS

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

The following data sets were generated
The following previously published data sets were used
    1. Guo H
    2. Zhu P
    3. Yan L
    4. Qiao J
    5. Tang F
    (2014) The DNA methylation landscape of human early embryos
    Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE49828).
    https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE49828

Article and author information

Author details

  1. Yixuan Wang

    School of Life Sciences and Technology, Tongji University, Shanghai, China
    For correspondence
    wangyixuan@tongji.edu.cn
    Competing interests
    The authors declare that no competing interests exist.

  2. Chengchen Zhao

    School of Life Sciences and Technology, Tongji University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  3. Zhenzhen Hou

    School of Life Sciences and Technology, Tongji University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  4. Yuanyuan Yang

    School of Life Sciences and Technology, Tongji University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  5. Yan Bi

    School of Life Sciences and Technology, Tongji University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  6. Hong Wang

    School of Life Sciences and Technology, Tongji University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  7. Yong Zhang

    School of Life Sciences and Technology, Tongji University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  8. Shaorong Gao

    School of Life Sciences and Technology, Tongji University, Shanghai, China
    For correspondence
    gaoshaorong@tongji.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1041-3928

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.

Reviewing Editor

  1. Martin Pera, University of Melbourne, Australia

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.

Version history

  1. Received: June 11, 2017
  2. Accepted: January 29, 2018
  3. Accepted Manuscript published: January 30, 2018 (version 1)
  4. Version of Record published: February 9, 2018 (version 2)

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.

Metrics

  • 3,581
    views
  • 684
    downloads
  • 36
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Yixuan Wang
  2. Chengchen Zhao
  3. Zhenzhen Hou
  4. Yuanyuan Yang
  5. Yan Bi
  6. Hong Wang
  7. Yong Zhang
  8. Shaorong Gao
(2018)
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

Share this article

https://doi.org/10.7554/eLife.29518

Categories and tags

Research organism

Further reading

    1. Stem Cells and Regenerative Medicine

    Long-term hematopoietic transfer of the anti-cancer and lifespan-extending capabilities of a genetically engineered blood system by transplantation of bone marrow mononuclear cells

    Jing-Ping Wang, Chun-Hao Hung ... C-K James Shen
    Research Article

    A causal relationship exists among the aging process, organ decay and disfunction, and the occurrence of various diseases including cancer. A genetically engineered mouse model, termed Klf1K74R/K74R or Klf1(K74R), carrying mutation on the well-conserved sumoylation site of the hematopoietic transcription factor KLF1/EKLF has been generated that possesses extended lifespan and healthy characteristics, including cancer resistance. We show that the healthy longevity characteristics of the Klf1(K74R) mice, as exemplified by their higher anti-cancer capability, are likely gender-, age-, and genetic background-independent. Significantly, the anti-cancer capability, in particular that against melanoma as well as hepatocellular carcinoma, and lifespan-extending property of Klf1(K74R) mice, could be transferred to wild-type mice via transplantation of their bone marrow mononuclear cells at a young age of the latter. Furthermore, NK(K74R) cells carry higher in vitro cancer cell-killing ability than wild-type NK cells. Targeted/global gene expression profiling analysis has identified changes in the expression of specific proteins, including the immune checkpoint factors PDCD and CD274, and cellular pathways in the leukocytes of the Klf1(K74R) that are in the directions of anti-cancer and/or anti-aging. This study demonstrates the feasibility of developing a transferable hematopoietic/blood system for long-term anti-cancer and, potentially, for anti-aging.

    1. Neuroscience
    2. Stem Cells and Regenerative Medicine

    SAFB regulates hippocampal stem cell fate by targeting Drosha to destabilize Nfib mRNA

    Pascal Forcella, Niklas Ifflander ... Verdon Taylor
    Research Article

    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.

    1. Stem Cells and Regenerative Medicine

    Disease modeling and pharmacological rescue of autosomal dominant retinitis pigmentosa associated with RHO copy number variation

    Sangeetha Kandoi, Cassandra Martinez ... Deepak A Lamba
    Research Article

    Retinitis pigmentosa (RP), a heterogenous group of inherited retinal disorder, causes slow progressive vision loss with no effective treatments available. Mutations in the rhodopsin gene (RHO) account for ~25% cases of autosomal dominant RP (adRP). In this study, we describe the disease characteristics of the first-ever reported mono-allelic copy number variation (CNV) in RHO as a novel cause of adRP. We (a) show advanced retinal degeneration in a male patient (68 years of age) harboring four transcriptionally active intact copies of rhodopsin, (b) recapitulated the clinical phenotypes using retinal organoids, and (c) assessed the utilization of a small molecule, Photoregulin3 (PR3), as a clinically viable strategy to target and modify disease progression in RP patients associated with RHO-CNV. Patient retinal organoids showed photoreceptors dysgenesis, with rod photoreceptors displaying stunted outer segments with occasional elongated cilia-like projections (microscopy); increased RHO mRNA expression (quantitative real-time PCR [qRT-PCR] and bulk RNA sequencing); and elevated levels and mislocalization of rhodopsin protein (RHO) within the cell body of rod photoreceptors (western blotting and immunohistochemistry) over the extended (300 days) culture time period when compared against control organoids. Lastly, we utilized PR3 to target NR2E3, an upstream regulator of RHO, to alter RHO expression and observed a partial rescue of RHO protein localization from the cell body to the inner/outer segments of rod photoreceptors in patient organoids. These results provide a proof-of-principle for personalized medicine and suggest that RHO expression requires precise control. Taken together, this study supports the clinical data indicating that RHO-CNV associated adRPdevelops as a result of protein overexpression, thereby overloading the photoreceptor post-translational modification machinery.