Retinoic Acid Signaling Is Essential for Embryonic Hematopoietic Stem Cell Development

Abstract

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.

Flow-induced protein kinase A–CREB pathway acts via BMP signaling to promote HSC emergence

“…Moreover, the PKA-CREB signaling pathway has been explored in the context of the prostaglandin E 2 signaling pathway in zebrafish, where it promotes AGM hematopoiesis via activation of the Wnt pathway ). However, whether this pathway is conserved in the mouse is unclear, especially given conflicting reports on Wnt signaling in AGM hematopoiesis (Ruiz-Herguido et al, 2012;Chanda et al, 2013). Prostaglandin E 2 also directly activates several pathways including PI3K-AKT and ERK-MAPK, which makes it difficult to conclude that PKA-CREB is the sole mediator of the pro-hematopoietic effects of this molecule (Alfranca et al, 2006).…”

Diverse Functions of Retinoic Acid in Brain Vascular Development

“…RA inhibits WNT signaling during hematopoietic stem cell development (Chanda et al, 2013) and in a variety of cancer cell lines with oncogenic ␤-catenin activity (Mulholland et al, 2005). Modulation of WNT signaling by RA signaling likely occurs at the level of RAR␣, which we show here is the main RAR expressed in fetal brain ECs.…”

“…RA signaling through its receptors has been shown to inhibit WNT signaling in a variety of cell types (Easwaran et al, 1999;Mulholland et al, 2005;Chanda et al, 2013), raising the possibility that RA may regulate WNT signaling directly in brain ECs. To begin to test this idea, we developed a mouse model in which RA signaling is specifically disrupted in brain ECs using an inducible EC-specific CreER T2 line (Pdgfbi-CreER T2 , referred to here as PdgfbiCre; Claxton et al, 2008) and a conditional, dominantnegative version of RAR␣ allele located in the ROSA26R locus (dnRAR403-flox) (Rosselot et al, 2010).…”

Concise Review: From Greenhouse to Garden: The Changing Soil of the Hematopoietic Stem Cell Microenvironment During Development

“…HSC induction in the AGM is primarily via RAR-a, while HSC expansion in the FL occurs through both RAR-a and RAR-c. Finally in adults, RAR-c is required for HSC maintenance [25][26][27].…”

“…RARa is the primary receptor mediating HSC expansion [27] HSC expansion occurs via both RARa and RARc in E13.5 fetal liver [27] RARc is essential for HSC maintenance [25,26] Abbreviations: AGM, aorta-gonads-mesonephros; HSC, hematopoietic stem cell.…”