Generation and trapping of a mesoderm biased state of human pluripotency

Dylan Stavish (), Charlotta Böiers, Christopher Price, Thomas J. R. Frith, Jason Halliwell, Ingrid Saldaña-Guerrero, Jason Wray, John Brown, Jonathon Carr, Chela James, Ivana Barbaric, Peter W. Andrews () and Tariq Enver
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Dylan Stavish: University of Sheffield, Western Bank
Charlotta Böiers: University College London Cancer Institute
Christopher Price: University of Sheffield, Western Bank
Thomas J. R. Frith: University of Sheffield, Western Bank
Jason Halliwell: University of Sheffield, Western Bank
Ingrid Saldaña-Guerrero: University of Sheffield, Western Bank
Jason Wray: University College London Cancer Institute
John Brown: University College London Cancer Institute
Jonathon Carr: University of Sheffield, Western Bank
Chela James: University College London Cancer Institute
Ivana Barbaric: University of Sheffield, Western Bank
Peter W. Andrews: University of Sheffield, Western Bank
Tariq Enver: University College London Cancer Institute

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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 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.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18727-8

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DOI: 10.1038/s41467-020-18727-8

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