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Title: Hemogenic endothelial cell specification requires c-kit, notch signaling, and p27-mediated cell-cycle control

Author
item MARCELO, KATHRINA - Baylor College Of Medicine
item SILLS, TIFFANY - Baylor College Of Medicine
item COSKUN, SULEYMAN - Yale University
item VASAVADA, HEMA - Yale University
item SANGLIKAR, SUPRIYA - Yale University
item GOLDIE, LAUREN - Children'S Nutrition Research Center (CNRC)
item HIRSCHI, KAREN - Yale University

Submitted to: Developmental Cell
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/4/2013
Publication Date: 12/9/2013
Citation: Marcelo, K.L., Sills, T.M., Coskun, S., Vasavada, H., Sanglikar, S., Goldie, L.C., Hirschi, K.K. 2013. Hemogenic endothelial cell specification requires c-kit, notch signaling, and p27-mediated cell-cycle control. Developmental Cell. 27(5):504-515.

Interpretive Summary: In previously published studies, we demonstrated that retinoic acid (RA), a derivative of vitamin A, is necessary for the development of a specialized type of vascular cell known as hemogenic endothelium. Hemogenic (blood-forming) endothelial cells give rise to the first blood stem cells of the developing embryo, which in turn produce all the different types of mature white blood cells needed for normal immune function. With their prevalence on the rise, blood and cardiovascular diseases are an increasingly significant public health concern with few new treatment options on the horizon. Our current understanding of the molecular signals which control the development of blood and vascular cells remains significantly lacking, and while emerging stem cell-based therapies hint at the potential to treat various blood and cardiovascular disorders in the future, greater understanding of the underlying biology of blood and vascular cell development remains crucial to this endeavor. These studies define a previously unknown molecular signaling pathway by which RA regulates the development of blood-forming endothelial cells from primitive vascular endothelial cells. Using a genetically-modified mouse model of RA deficiency, we showed that RA activates c-Kit, Notch, and p27 signaling proteins to restrict cell cycling (i.e. replication) in primitive vascular endothelial cells. Re-expression of p27 activity in RA-deficient and Notch-inactivated primitive endothelial cells was sufficient to compensate for loss of RA signaling, and enabled hemogenic endothelial cells to develop normally. These studies are the first to demonstrate a unique and critical role for RA-dependent cell cycle control in the development of hemogenic endothelial cells which are essential for normal blood formation. This knowledge contributes to our understanding of how the earliest blood cells develop at the molecular level, and will facilitate the development of new drug and stem cell-based therapies for a variety of blood and vascular disorders.

Technical 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.