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Generation and trapping of a mesoderm biased state of human pluripotency

Stavish, Dylan ; Böiers, Charlotta LU ; Price, Christopher ; Frith, Thomas J.R. ; Halliwell, Jason ; Saldaña-Guerrero, Ingrid ; Wray, Jason ; Brown, John ; Carr, Jonathon and James, Chela , et al. (2020) In Nature Communications 11.
Abstract

We postulate that exit from pluripotency involves intermediates that retain pluripotency while simultaneously exhibiting lineage-bias. Using a MIXL1 reporter, we explore mesoderm lineage-bias within the human pluripotent stem cell compartment. We identify a substate, which at the single cell level coexpresses pluripotent and mesodermal gene expression programmes. Functionally these cells initiate stem cell cultures and exhibit mesodermal bias in differentiation assays. By promoting mesodermal identity through manipulation of WNT signalling while preventing exit from pluripotency using lysophosphatidic acid, we ‘trap’ and maintain cells in a lineage-biased stem cell state through multiple passages. These cells correspond to a normal... (More)

We postulate that exit from pluripotency involves intermediates that retain pluripotency while simultaneously exhibiting lineage-bias. Using a MIXL1 reporter, we explore mesoderm lineage-bias within the human pluripotent stem cell compartment. We identify a substate, which at the single cell level coexpresses pluripotent and mesodermal gene expression programmes. Functionally these cells initiate stem cell cultures and exhibit mesodermal bias in differentiation assays. By promoting mesodermal identity through manipulation of WNT signalling while preventing exit from pluripotency using lysophosphatidic acid, we ‘trap’ and maintain cells in a lineage-biased stem cell state through multiple passages. These cells correspond to a normal state on the differentiation trajectory, the plasticity of which is evidenced by their reacquisition of an unbiased state upon removal of differentiation cues. The use of ‘cross-antagonistic’ signalling to trap pluripotent stem cell intermediates with different lineage-bias may have general applicability in the efficient production of cells for regenerative medicine.

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publishing date
type
Contribution to journal
publication status
published
in
Nature Communications
volume
11
article number
4989
publisher
Nature Publishing Group
external identifiers
  • pmid:33020476
  • scopus:85091963017
ISSN
2041-1723
DOI
10.1038/s41467-020-18727-8
language
English
LU publication?
no
id
6865a80f-8a45-4cf2-9387-77df0630d563
date added to LUP
2021-01-29 14:37:06
date last changed
2024-05-02 02:24:16
@article{6865a80f-8a45-4cf2-9387-77df0630d563,
  abstract     = {{<p>We postulate that exit from pluripotency involves intermediates that retain pluripotency while simultaneously exhibiting lineage-bias. Using a MIXL1 reporter, we explore mesoderm lineage-bias within the human pluripotent stem cell compartment. We identify a substate, which at the single cell level coexpresses pluripotent and mesodermal gene expression programmes. Functionally these cells initiate stem cell cultures and exhibit mesodermal bias in differentiation assays. By promoting mesodermal identity through manipulation of WNT signalling while preventing exit from pluripotency using lysophosphatidic acid, we ‘trap’ and maintain cells in a lineage-biased stem cell state through multiple passages. These cells correspond to a normal state on the differentiation trajectory, the plasticity of which is evidenced by their reacquisition of an unbiased state upon removal of differentiation cues. The use of ‘cross-antagonistic’ signalling to trap pluripotent stem cell intermediates with different lineage-bias may have general applicability in the efficient production of cells for regenerative medicine.</p>}},
  author       = {{Stavish, Dylan and Böiers, Charlotta and Price, Christopher and Frith, Thomas J.R. and Halliwell, Jason and Saldaña-Guerrero, Ingrid and Wray, Jason and Brown, John and Carr, Jonathon and James, Chela and Barbaric, Ivana and Andrews, Peter W. and Enver, Tariq}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  month        = {{12}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Generation and trapping of a mesoderm biased state of human pluripotency}},
  url          = {{http://dx.doi.org/10.1038/s41467-020-18727-8}},
  doi          = {{10.1038/s41467-020-18727-8}},
  volume       = {{11}},
  year         = {{2020}},
}