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

Kathrina L Marcelo; Tiffany M Sills; Suleyman Coskun; Hema Vasavada; Supriya Sanglikar; Lauren C Goldie; Karen K Hirschi

doi:10.1016/j.devcel.2013.11.004

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

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

Authors

Kathrina L Marcelo¹, Tiffany M Sills², Suleyman Coskun³, Hema Vasavada³, Supriya Sanglikar³, Lauren C Goldie¹, Karen K Hirschi⁴

Affiliations

¹ Interdepartmental 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.
² 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.
³ Yale Cardiovascular Research Center and Yale Stem Cell Center, Yale University School of Medicine, 300 George Street, New Haven, CT 06511, USA.
⁴ Interdepartmental 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Aldehyde Oxidoreductases / genetics
Animals
Antineoplastic Agents / pharmacology
Cell Cycle Checkpoints / physiology
Cell Differentiation / physiology
Core Binding Factor Alpha 2 Subunit / genetics
Cyclin-Dependent Kinase Inhibitor p27 / genetics
Cyclin-Dependent Kinase Inhibitor p27 / metabolism*
Embryo Culture Techniques
Endothelial Cells / cytology
Endothelial Cells / metabolism*
Female
Hematopoietic Stem Cells / cytology
Hematopoietic Stem Cells / metabolism*
Lac Operon
Lentivirus / genetics
Male
Mice
Mice, Knockout
Pregnancy
Proto-Oncogene Proteins c-kit / genetics
Proto-Oncogene Proteins c-kit / metabolism*
Proto-Oncogene Proteins c-myb / genetics
Receptor, Notch1 / metabolism*
Signal Transduction / drug effects
Signal Transduction / physiology*
Tretinoin / pharmacology

Substances

Antineoplastic Agents
Core Binding Factor Alpha 2 Subunit
Notch1 protein, mouse
Proto-Oncogene Proteins c-myb
Receptor, Notch1
Runx1 protein, mouse
Cyclin-Dependent Kinase Inhibitor p27
Tretinoin
Aldehyde Oxidoreductases
RALDH2 protein, mouse
Proto-Oncogene Proteins c-kit

Abstract

Publication types

MeSH terms

Substances

Grants and funding