In:
Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1283-1283
Abstract:
Abstract 1283 Adult hematopoietic cells transition through a hemogenic endothelial (HE) intermediate during development, but the signaling pathways modulating this transition are incompletely characterized. Although the Hedgehog (Hh) pathway is hypothesized to play a role in blood and endothelial cell formation, early embryonic lethality of mice lacking Hedgehog signaling precludes such analysis. To determine a role for Hh signaling in HE patterning, we assessed the effect of altered Hh signaling in differentiating mouse embryonic stem cells (mESCs), cultured embryonic day 9.5 mouse embryos, and developing zebrafish embryos. In differentiating mESCs, addition of Indian Hh ligand (IHH) increased the number of CD41+c-Kit+ hematopoietic progenitors, whereas chemical inhibition of Hh signaling led to a decrease without affecting primitive-streak mesoderm gene expression. In the setting of Hh inhibition, Notch induction rescued hemogenic VE-cadherin+ cells, demonstrating that Notch expands HE. Scl/Tal1 (stem cell leukemia/T-cell associated leukemia 1) induction rescued VE-cadherin+CD41+ cells, demonstrating that Scl/Tal1 converts endothelial cells to hematopoietic tissue. Similar experiments using cultured mouse yolk sacs demonstrated that signaling pathways are conserved in vivo. Moreover, VE-cadherin+ cells isolated from the mouse yolk sac or paraaortic splanchnopleura, when virally transduced with Notch signaling or Scl, had increased hematopoietic colony-forming activity. Finally, ectopic Notch or Scl induction in zebrafish embryos rescued the expression of the prototypical hemogenic endothelium marker Runx1 in the absence of Hh signalling. Together, our results reveal that the Hh-Notch-Scl axis promotes embryonic hematopoiesis through endothelial-to-hematopoietic transition. Disclosures: Zon: Fate Therapeutics: Consultancy; Stemgent: Consultancy. Daley:iPierian, Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Epizyme, Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Verastem, Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Solasia, KK: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; MPM Capital, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V118.21.1283.1283
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2011
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
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