Retinoic Acid Signaling Is Essential for Embryonic Hematopoietic Stem Cell Development

• Published in: Cell Vol. 155; no. 1; pp. 215 - 227
• Main Authors: Chanda, Bhaskar, Ditadi, Andrea, Iscove, Norman N., Keller, Gordon
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.09.2013
• Subjects: Aldehyde Oxidoreductases - metabolism; Animals; Aorta - cytology; Aorta - embryology; cells; Down-Regulation; Embryo, Mammalian; endothelial cells; endothelium; Gonads - cytology; Gonads - embryology; hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Mesonephros - cytology; Mice; Receptors, Retinoic Acid - metabolism; retinoic acid; signal transduction; Tretinoin - metabolism; Wnt Signaling Pathway
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2013.08.055

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. [Display omitted] •Retinal dehydrogenase 2 is required for hematopoietic stem cell specification•An aldefluor assay reveals retinal dehydrogenase activity in developing HSCs•RAR-alpha specifically mediates the inductive effect of retinoic acid on HSCs•RA signaling transiently inhibits Wnt signaling to promote embryonic HSC development Retinoic acid signaling is a key regulator of HSC development, promoting their generation through transient inhibition of Wnt signaling. These findings may aid the goal of generating HSCs from pluripotent stem cells.