Hartman Institute for Therapeutic Organ Regeneration

Smad1 signaling restricts hematopoietic potential after promoting hemangioblast commitment.

TitleSmad1 signaling restricts hematopoietic potential after promoting hemangioblast commitment.
Publication TypeJournal Article
Year of Publication2011
AuthorsCook BD, Liu S, Evans T
JournalBlood
Volume117
Issue24
Pagination6489-97
Date Published2011 Jun 16
ISSN1528-0020
KeywordsAnimals, Cell Differentiation, Cell Lineage, Cells, Cultured, Down-Regulation, Gene Knockdown Techniques, Hemangioblasts, Hematopoiesis, Hematopoietic Stem Cells, Humans, Mice, Models, Biological, Signal Transduction, Smad1 Protein
Abstract

<p>Bone morphogenetic protein (BMP) signaling regulates embryonic hematopoiesis via receptor-mediated activation of downstream SMAD proteins, including SMAD1. In previous work, we showed that Smad1 expression is sufficient to enhance commitment of mesoderm to hemangioblast fate. We also found indirect evidence to support a subsequent repressive function for Smad1 in hematopoiesis. To test this hypothesis directly, we developed a novel system allowing temporal control of Smad1 levels by conditional knockdown in embryonic stem cell derivatives. Depletion of Smad1 in embryoid body cultures before hemangioblast commitment limits hematopoietic potential because of a block in mesoderm development. Conversely, when Smad1 is depleted in FlK1(+) mesoderm, at a stage after hemangioblast commitment, the pool of hematopoietic progenitors is expanded. This involves enhanced expression levels for genes specific to hematopoiesis, including Gata1, Runx1 and Eklf, rather than factors required for earlier specification of the hemangioblast. The phenotype correlates with increased nuclear SMAD2 activity, indicating molecular cross-regulation between the BMP and TGF-β signaling pathways. Consistent with this mechanism, hematopoiesis was enhanced when Smad2 was directly expressed during this same developmental window. Therefore, this study reveals a temporally defined function for Smad1 in restricting the expansion of early hematopoietic progenitors.</p>

DOI10.1182/blood-2010-10-312389
Alternate JournalBlood
PubMed ID21515822
PubMed Central IDPMC3123019
Grant ListT32 HL083824 / HL / NHLBI NIH HHS / United States
R37HL056182 / HL / NHLBI NIH HHS / United States
T32HL083824 / HL / NHLBI NIH HHS / United States
R37 HL056182 / HL / NHLBI NIH HHS / United States
R37 HL056182-15 / HL / NHLBI NIH HHS / United States

Weill Cornell Medicine
Hartman Institute for Therapeutic Organ Regeneration
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