Transcription Factor Levels after Forward Programming of Human Pluripotent Stem Cells with GATA1, FLI1, and TAL1 Determine Megakaryocyte versus Erythroid Cell Fate Decision.
Tijssen, Marloes R
Stem Cell Reports
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Dalby, A., Ballester-Beltrán, J., Lincetto, C., Mueller, A., Foad, N., Evans, A., Baye, J., et al. (2018). Transcription Factor Levels after Forward Programming of Human Pluripotent Stem Cells with GATA1, FLI1, and TAL1 Determine Megakaryocyte versus Erythroid Cell Fate Decision.. Stem Cell Reports, 11 (6), 1462-1478. https://doi.org/10.1016/j.stemcr.2018.11.001
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.
Megakaryocytes, Cells, Cultured, Erythroid Cells, Pluripotent Stem Cells, Humans, Erythropoietin, Thrombopoietin, Cytokines, Cell Differentiation, Gene Silencing, Cell Lineage, Transgenes, GATA1 Transcription Factor, Proto-Oncogene Protein c-fli-1, T-Cell Acute Lymphocytic Leukemia Protein 1
We acknowledge funding from the BHF Cambridge Centre of Excellence (RE/13/6/30180), the Wellcome Trust (Novosang consortium) and the NHS Blood and Transplant Service
Wellcome Trust (via Scottish National Blood Transfusion Service (SNTBS)) (XXL9126634)
Medical Research Council (MC_PC_12009)
British Heart Foundation (None)
MRC (MC_PC_14116 v2)
External DOI: https://doi.org/10.1016/j.stemcr.2018.11.001
This record's URL: https://www.repository.cam.ac.uk/handle/1810/287363
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/