Capture of Mouse and Human Stem Cells with Features of Formative Pluripotency

Kinoshita, Masaki; Barber, Michael; Mansfield, William; Cui, Yingzhi; Spindlow, Daniel; Stirparo, Giuliano Giuseppe; Dietmann, Sabine; Nichols, Jennifer; Smith, Austin

Abstract

Pluripotent cells emerge as a naive founder population in the blastocyst, acquire capacity for germline and soma formation, and then undergo lineage priming. Mouse embryonic stem cells (ESCs) and epiblast-derived stem cells (EpiSCs) represent the initial naive and final primed phases of pluripotency, respectively. Here, we investigate the intermediate formative stage. Using minimal exposure to specification cues, we derive stem cells from formative mouse epiblast. Unlike ESCs or EpiSCs, formative stem (FS) cells respond directly to germ cell induction. They colonize somatic tissues and germline in chimeras. Whole-transcriptome analyses show similarity to pre-gastrulation formative epiblast. Signal responsiveness and chromatin accessibility features reflect lineage capacitation. Furthermore, FS cells show distinct transcription factor dependencies, relying critically on Otx2. Finally, FS cell culture conditions applied to human naive cells or embryos support expansion of similar stem cells, consistent with a conserved staging post on the trajectory of mammalian pluripotency.

Citation

Kinoshita, M., Barber, M., Mansfield, W., Cui, Y., Spindlow, D., Stirparo, G. G., Dietmann, S., Nichols, J., & Smith, A. (2021). Capture of Mouse and Human Stem Cells with Features of Formative Pluripotency. Cell Stem Cell, 28(3), 453-471. https://doi.org/10.1016/j.stem.2020.11.005

• Journal Article Type: Article
• Acceptance Date: Nov 9, 2020
• Online Publication Date: Dec 2, 2020
• Publication Date: 2021-03
• Deposit Date: Mar 5, 2025
• Publicly Available Date: Mar 6, 2025
• Journal: Cell Stem Cell
• Print ISSN: 1934-5909
• Electronic ISSN: 1875-9777
• Publisher: Cell Press
• Peer Reviewed: Peer Reviewed
• Volume: 28
• Issue: 3
• Pages: 453-471
• DOI: https://doi.org/10.1016/j.stem.2020.11.005
• Keywords: pluripotent stem cell, epiblast, formative pluripotency, primordial germ cell, chimaera, self-renewal, lineage induction
• Public URL: https://nottingham-repository.worktribe.com/output/46190254
• Publisher URL: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30543-9?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1934590920305439%3Fshowall%3Dtrue
• Additional Information: This article is maintained by: Elsevier; Article Title: Capture of Mouse and Human Stem Cells with Features of Formative Pluripotency; Journal Title: Cell Stem Cell; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.stem.2020.11.005; CrossRef DOI link to the associated document: https://doi.org/10.1016/j.stem.2020.11.003; Content Type: article; Copyright: © 2020 The Authors. Published by Elsevier Inc.