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Dev Cell. 2013 Dec 9;27(5):504-15. doi: 10.1016/j.devcel.2013.11.004.

Hemogenic endothelial cell specification requires c-Kit, Notch signaling, and p27-mediated cell-cycle control.

Author information

  • 1Interdepartmental Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Children's Nutrition Research Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
  • 2Interdisciplinary Program in Cell and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Children's Nutrition Research Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
  • 3Yale Cardiovascular Research Center and Yale Stem Cell Center, Yale University School of Medicine, 300 George Street, New Haven, CT 06511, USA.
  • 4Interdepartmental Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Interdisciplinary Program in Cell and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Children's Nutrition Research Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Yale Cardiovascular Research Center and Yale Stem Cell Center, Yale University School of Medicine, 300 George Street, New Haven, CT 06511, USA. Electronic address: karen.hirschi@yale.edu.

Abstract

Delineating the mechanism or mechanisms that regulate the specification of hemogenic endothelial cells from primordial endothelium is critical for optimizing their derivation from human stem cells for clinical therapies. We previously determined that retinoic acid (RA) is required for hemogenic specification, as well as cell-cycle control, of endothelium during embryogenesis. Herein, we define the molecular signals downstream of RA that regulate hemogenic endothelial cell development and demonstrate that cell-cycle control is required for this process. We found that re-expression of c-Kit in RA-deficient (Raldh2(-/-)) primordial endothelium induced Notch signaling and p27 expression, which restored cell-cycle control and rescued hemogenic endothelial cell specification and function. Re-expression of p27 in RA-deficient and Notch-inactivated primordial endothelial cells was sufficient to correct their defects in cell-cycle regulation and hemogenic endothelial cell development. Thus, RA regulation of hemogenic endothelial cell specification requires c-Kit, notch signaling, and p27-mediated cell-cycle control.

Copyright © 2013 Elsevier Inc. All rights reserved.

PMID:
24331925
[PubMed - indexed for MEDLINE]
PMCID:
PMC3994666
Free PMC Article

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