Generation and trapping of a mesoderm biased state of human pluripotency

Research output: Contribution to journalArticle

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.

Details

Authors
  • 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
  • Tariq Enver
External organisations
  • University of Sheffield
  • University College London
Original languageEnglish
Article number4989
JournalNature Communications
Volume11
Publication statusPublished - 2020 Dec 1
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes