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- Title
Inducible Gata1 suppression expands megakaryocyte-erythroid progenitors from embryonic stem cells.
- Authors
Ji-Yoon Noh; Gandre-Babbe, Shilpa; Yuhuan Wang; Hayes, Vincent; Yu Yao; Gadue, Paul; Sullivan, Spencer K.; Chou, Stella T.; Machlus, Kellie R.; Italiano Jr., Joseph E.; Kyba, Michael; Finkelstein, David; Ulirsch, Jacob C.; Sankaran, Vijay G.; French, Deborah L.; Poncz, Mortimer; Weiss, Mitchell J.
- Abstract
Transfusion of donor-derived platelets is commonly used for thrombocytopenia, which results from a variety of clinical conditions and relies on a constant donor supply due to the limited shelf life of these cells. Embryonic stem (ES) and induced pluripotent stem (iPS) cells represent a potential source of megakaryocytes and platelets for transfusion therapies; however, the majority of current ES/iPS cell differentiation protocols are limited by low yields of hematopoietic progeny. In both mice and humans, mutations in the gene-encoding transcription factor GATA1 cause an accumulation of proliferating, developmentally arrested megakaryocytes, suggesting that GATA1 suppression in ES and iPS cell--derived hematopoietic progenitors may enhance megakaryocyte production. Here, we engineered ES cells from WT mice to express a doxycycline-regulated (dox-regulated) shRNA that targets Gata1 transcripts for degradation. Differentiation of these cells in the presence of dox and thrombopoietin (TPO) resulted in an exponential (at least 1013-fold) expansion of immature hematopoietic progenitors. Dox withdrawal in combination with multilineage cytokines restored GATA1 expression, resulting in differentiation into erythroblasts and megakaryocytes. Following transfusion into recipient animals, these dox-deprived mature megakaryocytes generated functional platelets. Our findings provide a readily reproducible strategy to exponentially expand ES cell--derived megakaryocyte-erythroid progenitors that have the capacity to differentiate into functional platelet-producing megakaryocytes.
- Subjects
EMBRYONIC stem cell research; BLOOD platelet transfusion; THROMBOCYTOPENIA treatment; BLOOD platelet disorders; PLURIPOTENT stem cells; BLOOD disease treatment; THERAPEUTICS
- Publication
Journal of Clinical Investigation, 2015, Vol 125, Issue 6, p2369
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI77670