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Role of Vitamin A/Retinoic Acid in Regulation of Embryonic and Adult Hematopoiesis

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Role of Vitamin A/Retinoic Acid in Regulation of Embryonic and Adult Hematopoiesis nutrients Review Role of Vitamin A/Retinoic Acid in Regulation of Embryonic and Adult Hematopoiesis Ana Cañete 1, Elena Cano 2, Ramón Muñoz-Chápuli 1 and Rita Carmona 1,* 1 Department of Animal Biology, Faculty of Science, University of Malaga, Campus de Teatinos s/n Malaga 29071, Spain and Andalusian Center for Nanomedicine and Biotechnology (BIONAND), Severo Ochoa 25, Campanillas 29590, Spain; [email protected] (A.C.); [email protected] (R.M.-C.) 2 Max-Delbruck Center for Molecular Medicine, Robert Roessle-Strasse 10, 13125 Berlin, Germany; [email protected] * Correspondence: [email protected]; Tel.: +34-952134135; Fax: +34-952131668 Received: 23 October 2016; Accepted: 16 February 2017; Published: 20 February 2017 Abstract: Vitamin A is an essential micronutrient throughout life. Its physiologically active metabolite retinoic acid (RA), acting through nuclear retinoic acid receptors (RARs), is a potent regulator of patterning during embryonic development, as well as being necessary for adult tissue homeostasis. Vitamin A deficiency during pregnancy increases risk of maternal night blindness and anemia and may be a cause of congenital malformations. Childhood Vitamin A deficiency can cause xerophthalmia, lower resistance to infection and increased risk of mortality. RA signaling appears to be essential for expression of genes involved in developmental hematopoiesis, regulating the endothelial/blood cells balance in the yolk sac, promoting the hemogenic program in the aorta-gonad-mesonephros area and stimulating eryrthropoiesis in fetal liver by activating the expression of erythropoietin. In adults, RA signaling regulates differentiation of granulocytes and enhances erythropoiesis. Vitamin A may facilitate iron absorption and metabolism to prevent anemia and plays a key role in mucosal immune responses, modulating the function of regulatory T cells. Furthermore, defective RA/RARα signaling is involved in the pathogenesis of acute promyelocytic leukemia due to a failure in differentiation of promyelocytes. This review focuses on the different roles played by vitamin A/RA signaling in physiological and pathological mouse hematopoiesis duddurring both, embryonic and adult life, and the consequences of vitamin A deficiency for the blood system. Keywords: vitamin A; retinoic acid; hematopoiesis; embryos; leukemia; vitamin A deficiency 1. Introduction Vitamin A was discovered in the second decade of the twentieth century by Elmer McCollum and Marguerite Davis [1]; also known as retinol, it is one of the fat soluble vitamins, and plays an important role in vision, reproduction, immune function, as well as cell growth and communication [2–10]. Vitamin A, regarded as an important micronutrient in mammalian diet, exists in three forms: retinal, retinol and retinoic acid (RA), the latter being the most metabolically active. Dietary vitamin A is obtained from plant sources (provitamin A carotenoids, particularly β-carotene) or as retinyl esters from animal sources, fortified food products and supplements. The metabolic fate of this retinol is the esterification and tissue storage (primarily in the liver), or the irreversible oxidation to all-trans retinaldehyde and to all-trans retinoic acid (ATRA) by alcohol and aldehyde deshydrogenases. In mammals, this latter family of enzymes includes three cytosolic aldehyde dehydrogenases: RALDH1 (encoded by the ALDH1A1 gene) [11], RALDH2 (ALDH1A2), which is the main RA-synthesizing enzyme in the mesoderm [12], and RALDH3 (ALDH1A3)[13–15]. Nutrients 2017, 9, 159; doi:10.3390/nu9020159 www.mdpi.com/journal/nutrients Nutrients 2017, 9, 159 2 of 18 Nutrients 2017, 9, 159 2 of 17 RARA signaling signaling is is mediated mediated by by two two families families of nuclear receptors: receptors: RARs RARs and and RXRs, RXRs, including including three three membersmembersα, αβ, β andandγ γ forfor each each family family [16]. [16 ].Nuclear Nuclear retinoid retinoid receptors receptors are frequently are frequently composed composed of RXR of RXRand and RAR RAR heterodimers, heterodimers, although although RXRs RXRscan form can homodimers form homodimers or heterodimers or heterodimers with other with nuclear other nuclearreceptors receptors such as such the vitamin as the D vitamin receptor, D as receptor, discussed as below, discussed or PPARs below, (peroxisome or PPARs proliferator (peroxisome‐ activated receptors). In the nucleus, the RAR/RXR complex is bound to a specific sequence of DNA proliferator-activated receptors). In the nucleus, the RAR/RXR complex is bound to a specific sequence (RARE: retinoic acid response element) and usually performs repressor roles in the absence of of DNA (RARE: retinoic acid response element) and usually performs repressor roles in the absence of ligands, activating transcription of target genes when bound to them ([16,17]) (Figure 1). ligands, activating transcription of target genes when bound to them ([16,17]) (Figure1). Figure 1. Role of vitamin A/retinol in adult hematopoiesis. This picture shows the main molecular Figure 1. Role of vitamin A/retinol in adult hematopoiesis. This picture shows the main molecular pathways leading from the vitamin A sources to the target genes of the retinoic acid (RA, the active pathways leading from the vitamin A sources to the target genes of the retinoic acid (RA, the active form of vitamin A) related with hematopoiesis in the tissues. Retinol or provitamin A is ingested and formabsorbed of vitamin through A) related the intestine, with hematopoiesis transported by retinol in the‐ tissues.binding Retinolproteins or and provitamin stored in the A liver. is ingested Retinol and absorbedis transformed through by the the intestine, cells into transported RA by alcohol by retinol-binding and aldehyde dehydrogenases proteins and stored (ADHs in theand liver. RALDHs Retinol is transformedrespectively). by RA the is cellstransported into RA by by cellular alcohol retinoic and aldehyde acid binding dehydrogenases proteins (CRABP) (ADHs and and it RALDHscan be respectively).degraded by RA CYP26 is transported or translocated by to cellular the nucleus, retinoic where acid it bindingbinds and proteins activates (CRABP) nuclear retinoid and it acid can be degradedreceptors by (RARs CYP26 and or RXRs), translocated displacing to the co nucleus,‐repressors where and recruiting it binds and coactivators activates of nuclear the transcription retinoid acid receptorsof target (RARs genes. and In this RXRs), way, displacing RA regulates co-repressors the developmental and recruiting hematopoiesis, coactivators modulates of the lympho transcription and of targetgranulopoiesis genes. In and this contributes way, RA regulatesto the homeostasis the developmental of the hematopoietic hematopoiesis, stem cells. modulates Vitamin D lympho receptor and granulopoiesis(VDR) can also and dimerize contributes with toRXRs the and homeostasis modulate of the the immune hematopoietic response. stem cells. Vitamin D receptor (VDR) can also dimerize with RXRs and modulate the immune response. Vitamin A deficiency is widespread in developing countries [8]. Besides prominent ocular consequences of this deficiency (e.g., xerophthalmia), anemia and immune deficiency highlight other Vitamin A deficiency is widespread in developing countries [8]. Besides prominent ocular critical roles of vitamin A/RA signaling [5,6]. Furthermore, RA signaling is crucially involved in the consequences of this deficiency (e.g., xerophthalmia), anemia and immune deficiency highlight other pathogenesis but also in the treatment of some types of leukemia [18,19]. For these reasons, in this critical roles of vitamin A/RA signaling [5,6]. Furthermore, RA signaling is crucially involved review we aim to provide the readers with an update on the functions played by vitamin A/RA insignaling the pathogenesis in the development, but also inhomeostasis the treatment and pathology of some of types the hematopoietic of leukemia system. [18,19]. An For earlier these reasons,report inof this our review group we mainly aim tofocused provide on the the readers functions with of an RA update signaling on the for functions developmental played by vitamin A/RA signaling in the development, homeostasis and pathology of the hematopoietic system. An earlier report of our group mainly focused on the functions of RA signaling for developmental Nutrients 2017, 9, 159 3 of 18 Nutrients 2017, 9, 159 3 of 17 hematopoiesishematopoiesis [ 20[20].]. InIn thisthis review, mainly focused focused on on the the mouse mouse model, model, we we pay pay more more attention attention to to essentialessential roles roles played played by by vitamin vitamin A in the hematopoietic hematopoietic system. system. 2.2. Vitamin Vitamin A/Retinoic A/Retinoic Acid Acid inin DevelopmentalDevelopmental Hematopoiesis Hematopoiesis RARA signaling signaling playsplays anan essentialessential role role in in vascular vascular development development and and in inthe the early early embryonic embryonic hematopoiesis.hematopoiesis. In In the the mouse mouse embryo, hematopoiesis hematopoiesis starts starts around around E7.0–E7.5, E7.0–E7.5, when when a first a first generation generation ofof primitive primitive erythroid erythroid cellscells andand endothelial cells cells forms forms clusters clusters or or blood blood-islands‐islands in the in the splanchnic splanchnic mesodermmesoderm of of the the yolk yolk sac.sac. Later, these clusters clusters connect connect with with the the developing developing vessels vessels of the of theembryo.
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