Retinoic acid signaling is essential for embryonic hematopoietic stem cell development.
Hematopoietic stem cells (HSCs) develop from a specialized subpopulation of endothelial cells known as hemogenic endothelium (HE). Although the HE origin of HSCs is now well established in different species, the signaling pathways that control this transition remain poorly understood. Here, we show that activation of retinoic acid (RA) signaling in aorta-gonad-mesonephros-derived HE ex vivo dramatically enhanced its HSC potential, whereas conditional inactivation of the RA metabolizing enzyme retinal dehydrogenase 2 in VE-cadherin expressing endothelial cells in vivo abrogated HSC development. Wnt signaling completely blocked the HSC inductive effects of RA modulators, whereas inhibition of the pathway promoted the development of HSCs in the absence of RA signaling. Collectively, these findings position RA and Wnt signaling as key regulators of HSC development and in doing so provide molecular insights that will aid in developing strategies for their generation from pluripotent stem cells.
McEwen Centre for Regenerative Medicine, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
Bhaskar
B
Chanda
Andrea
A
Ditadi
Norman N
NN
Iscove
Gordon
G
Keller
D000445:Aldehyde Oxidoreductases / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000196:embryology; D015536:Down-Regulation; D004622:Embryo, Mammalian; D006066:Gonads / Q000166:cytology / Q000196:embryology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D008650:Mesonephros / Q000166:cytology; D051379:Mice; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism*; D060449:Wnt Signaling Pathway
D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D000445:Aldehyde Oxidoreductases; C470579:RALDH2 protein, mouse