Vitamin A-Retinoic Acid Signaling Regulates Hematopoietic Stem Cell Dormancy

Cabezas-Wallscheid, Nina; Buettner, Florian; Sommerkamp, Pia; Klimmeck, Daniel; Ladel, Luisa; Thalheimer, Frederic B.; Pastor-Flores, Daniel; Roma, Letícia Prates; Renders, Simon; Zeisberger, Petra; Przybylla, Adriana; Schönberger, Katharina; Scognamiglio, Roberta; Altamura, Sandro; Florian, Carolina M.; Fawaz, Malak; Vonficht, Dominik; Tesio, Melania; Collier, Paul; Pavlinic, Dinko; Geiger, Hartmut; Schroeder, Timm; Beneš, Vladimı́r; Dick, Tobias P.; Rieger, Michael A.; Stegle, Oliver; Trumpp, Andreas

doi:10.1016/j.cell.2017.04.018

Cited by 368 publications

(312 citation statements)

References 82 publications

(124 reference statements)

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“…When RA is limited via dietary uptake, HSC are activated to proliferate and differentiate. 79 This is in line with findings that loss of the RA receptor retinoic acid receptor c (RARc) leads to decreased HSC number and increased differentiation. 80 The same study also showed that RARc activation increases the self-renewing capacity of HSC.…”

Section: Amino Acids a Keystone For Bm And Immune Cell Differentiatisupporting

confidence: 83%

Local exchange of metabolites shapes immunity

2018

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SummaryImmune cell differentiation and function depend on metabolic changes for the provision of energy and metabolites. Consequently, cellular metabolism relies on the availability of micronutrients such as vitamins and energy‐rich sources including amino acids and fatty acids. The bone marrow controls the continuous production of blood cells and is thereby reliant on the sophisticated interplay of progenitor and mature immune cells with its stromal microenvironment. The significance of stromal subsets in immunopoiesis is undisputed; however, our current knowledge is limited to their role in the production and secretion of a variety of soluble proteins such as cytokines. In contrast, the role of the haematopoietic niche in controlling and providing nutrients such as fatty acids, amino acids and vitamins, which are required for immune cell differentiation and function, remains largely elusive. In this review, we summarize the current understanding of local nutritional exchange and control between immune and stromal cells in peripheral tissue and, when it is known, in the bone marrow. The parallels found between peripheral tissues and bone marrow stroma raises the question of how local metabolism is capable of influencing haematopoiesis and immunopoiesis. A better understanding of the local exchange of nutrients in the bone marrow can be used to improve immune cell formation during ageing, after haematopoietic stem cell transplantation and during immune challenge.

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Section: Amino Acids a Keystone For Bm And Immune Cell Differentiatisupporting

confidence: 83%

Local exchange of metabolites shapes immunity

2018

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“…Deletion of this element globally reduced HoxB expression in HSCs, resulting in changes to downstream signaling pathways, and loss of HSC selfrenewal and reconstitution capacity (Qian et al, 2018). These findings demonstrate pivotal roles for RA signaling in the stem cell niche (Cabezas-Wallscheid et al, 2017;Chanda, Ditadi, Iscove, & Keller, 2013;Ghiaur et al, 2013;Qian et al, 2018) Table 1). There are several RAREs found within and immediately flanking the Hox complexes (Figures 2 and 4).…”

Section: Ra Signaling and Hox Gene Regulation In The Hematopoietic mentioning

confidence: 86%

Hox genes: Downstream “effectors” of retinoic acid signaling in vertebrate embryogenesis

Nolte

Kumar

Krumlauf

2019

Genesis

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Summary One of the major regulatory challenges of animal development is to precisely coordinate in space and time the formation, specification, and patterning of cells that underlie elaboration of the basic body plan. How does the vertebrate plan for the nervous and hematopoietic systems, heart, limbs, digestive, and reproductive organs derive from seemingly similar population of cells? These systems are initially established and patterned along the anteroposterior axis (AP) by opposing signaling gradients that lead to the activation of gene regulatory networks involved in axial specification, including the Hox genes. The retinoid signaling pathway is one of the key signaling gradients coupled to the establishment of axial patterning. The nested domains of Hox gene expression, which provide a combinatorial code for axial patterning, arise in part through a differential response to retinoic acid (RA) diffusing from anabolic centers established within the embryo during development. Hence, Hox genes are important direct effectors of retinoid signaling in embryogenesis. This review focuses on describing current knowledge on the complex mechanisms and regulatory processes, which govern the response of Hox genes to RA in several tissue contexts including the nervous system during vertebrate development.

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“…To this end, several groups have confirmed the pro-differentiation role of retinoids on human HSCs [47, 48] while elegant studies in murine models have shown the opposite effects [49, 50]. While in-depth studies to explain these interspecies differences are lacking, analysis of published data hint towards potential explanations for observed differences.…”

Section: Regulation Of Stemness By the Microenvironment’s Control Of Ramentioning

confidence: 99%

Retinoic acid, CYP26, and drug resistance in the stem cell niche

Alonso

Jones

Ghiaur

2017

Experimental Hematology

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The bone marrow niche is essential for hematopoietic stem cells to maintain lifelong blood production, by balancing their self-renewal and differentiation. Hematologic malignancies have a similar hierarchical organization to their normal counterparts, with rare populations of cancer stem cells that rely on the microenvironment to survive and propagate their differentiated malignant progenitor cells. Cancer cells alter their microenvironment to create a supportive niche where they endure chemotherapy, survive as minimal residual disease, and eventually prevail at relapse. Powerful morphogens such as retinoids, Wnt/βcatenin, Notch and Hedgehog control stem cell fates across tissues including normal and malignant hematopoiesis. The molecular conversations between these pathways as well as the mechanisms that control their activity and create gradients at cellular scale remain a mystery. Here, we discuss accumulating evidence that suggests that CYP26, the primary retinoid-inactivating enzyme, plays a critical role in the integration of two of these molecular programs: the retinoid and Hedgehog pathways. Induction of stromal CYP26 by either one of these pathways limits retinoic acid concentration in the stem cell niche with profound effects on tissue homeostasis and drug resistance. Bypassing this gatekeeping mechanism holds promise for overcoming drug resistance and improving clinical outcomes in hematological malignancies and cancer in general.

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Vitamin A-Retinoic Acid Signaling Regulates Hematopoietic Stem Cell Dormancy

Cited by 368 publications

References 82 publications

Local exchange of metabolites shapes immunity

Local exchange of metabolites shapes immunity

Hox genes: Downstream “effectors” of retinoic acid signaling in vertebrate embryogenesis

Retinoic acid, CYP26, and drug resistance in the stem cell niche

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