Transcription Factor Levels after Forward Programming of Human Pluripotent Stem Cells with GATA1, FLI1, and TAL1 Determine Megakaryocyte versus Erythroid Cell Fate Decision

Research output: Contribution to journalArticlepeer-review

Authors

  • Jose Ballester-Beltran
  • Chiara Lincetto
  • Annett Muller
  • Nicola Foad
  • Amanda Evans
  • James Baye
  • Ernest Turro
  • Thomas Moreau
  • Marloes Tijssen
  • Cedric Ghevaert

Colleges, School and Institutes

External organisations

  • University of Cambridge

Abstract

Summary
The production of blood cells and their precursors from human pluripotent stem cells (hPSCs) in vitro has the potential to make a significant impact upon healthcare provision. We demonstrate that the forward programming of hPSCs through overexpression of GATA1, FLI1, and TAL1 leads to the production of a population of progenitors that can differentiate into megakaryocyte or erythroblasts. Using “rainbow” lentiviral vectors to quantify individual transgene expression in single cells, we demonstrate that the cell fate decision toward an erythroblast or megakaryocyte is dictated by the level of FLI1 expression and is independent of culture conditions. Early FLI1 expression is critical to confer proliferative potential to programmed cells while its subsequent silencing or maintenance dictates an erythroid or megakaryocytic fate, respectively. These committed progenitors subsequently expand and mature into megakaryocytes or erythroblasts in response to thrombopoietin or erythropoietin. Our results reveal molecular mechanisms underlying hPSC forward programming and novel opportunities for application to transfusion medicine.

Details

Original languageEnglish
Pages (from-to)1462-1478
JournalStem Cell Reports
Volume11
Issue number6
Publication statusPublished - 11 Dec 2018

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