Review
Emerging roles for retinoids in regeneration and differentiation in normal and disease states

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Abstract

The vitamin A (retinol) metabolite, all-trans retinoic acid (RA), is a signaling molecule that plays key roles in the development of the body plan and induces the differentiation of many types of cells. In this review the physiological and pathophysiological roles of retinoids (retinol and related metabolites) in mature animals are discussed. Both in the developing embryo and in the adult, RA signaling via combinatorial Hox gene expression is important for cell positional memory. The genes that require RA for the maturation/differentiation of T cells are only beginning to be cataloged, but it is clear that retinoids play a major role in expression of key genes in the immune system. An exciting, recent publication in regeneration research shows that ALDH1a2 (RALDH2), which is the rate-limiting enzyme in the production of RA from retinaldehyde, is highly induced shortly after amputation in the regenerating heart, adult fin, and larval fin in zebrafish. Thus, local generation of RA presumably plays a key role in fin formation during both embryogenesis and in fin regeneration. HIV transgenic mice and human patients with HIV-associated kidney disease exhibit a profound reduction in the level of RARβ protein in the glomeruli, and HIV transgenic mice show reduced retinol dehydrogenase levels, concomitant with a greater than 3-fold reduction in endogenous RA levels in the glomeruli. Levels of endogenous retinoids (those synthesized from retinol within cells) are altered in many different diseases in the lung, kidney, and central nervous system, contributing to pathophysiology. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism.

Highlights

► RA signaling via Hox expression is important for cell positional memory. ► ALDH1a2 (RALDH2) is induced after amputation in the regenerating heart and fin in zebrafish. ► Endogenous retinoids are altered in many different diseases in adult animals.

Section snippets

Retinoids are stored in cells and active retinoids are generated locally to regulate gene expression

The vitamin A (retinol) metabolite, all-trans retinoic acid (RA), is a signaling molecule that plays key roles in the development of the body plan and induces the differentiation of many types of cells [1], [2], [3]. This review will focus on recent discoveries about the roles of retinoids in specific tissues. Although much remains to be learned, a basic outline of RA's molecular mechanisms of action has been established (Fig. 1). Retinol is obtained from our diet — we can't synthesize retinol

Differentiation of Foxp3+ regulatory T cells in the intestine requires the metabolic conversion of retinol to retinoic acid: the role of mucosal dendritic cells

Foxp3+ regulatory T cells (Tregs) are essential for the establishment and maintenance of immune tolerance. Many Tregs develop their regulatory activity in the thymus, but Foxp3+ Tregs (CD4(+) CD25(+) Foxp3+ T cells) can also differentiate from naive precursor/progenitor cells in the periphery. Over the past few years a role for endogenous RA in the regulation of the differentiation of these naive precursor cells has begun to be delineated. Recent work has demonstrated that stimulation of the

Retinoid response elements in immune genes

Like the Foxp3 gene (see above), the murine CCR9 gene has a RA response element half-site in its 5′-flanking region to which the RAR/RXR heterodimer complex binds, and the presence of this site is critical for RA-induced promoter activity. In addition, the transcription factor nuclear factor activator of T cells isoform 2 (NFATc2) directly binds to RARα and RXRα, and NFATc2 enhances the binding of RARα to the RA response element half-site in the CCR9 promoter in murine naïve CD4+ T-cells [33].

RA and the differentiation of dendritic cells (DCs)

Another aspect of the actions of dendritic cells became clearer when Feng et al [22] demonstrated that a subset of cells in the bone marrow express the retinoic acid (RA)-synthesizing enzyme ALDH1a2 and are able to provide RA to DC precursors in the bone marrow. These bone marrow-derived DCs then differentiate further, resulting in both increased expression of CCR9 and ALDH1a2 and an increase in mucosal DC markers and actions; these mucosal DC activities include induction of Foxp3+ regulatory T

Inflammation, retinoids, and ABC transporters

Endogenous retinoids are essential for the maturation and function of many cells of the immune system. RA, produced by DCs, plays a major role in the regulation of the differentiation of CD4+ naïve T-cells into Foxp3+Treg cells (Fig. 2). Open questions include how RA is transported out of DCs and into T-cells; how RA is synthesized at the proper level to allow a balanced immune response; and how the RA signal is turned off in these cells. In this context the retinaldehyde ABC family transporter

Endogenous RA regulates the differentiation of memory B cells

The synthesis of RA from retinol is also necessary for regulating the transcription factor NFATc1 expression and for the differentiation and maintenance of the natural memory B cell compartment [43]. B1 cells are a subtype of B cells that generates the majority of the natural serum IgM and the gut IgA antibodies; thus, B1 cells constitute a key component of early immune responses to pathogens. A vitamin A-deficient diet greatly reduces NFATc1 expression in B1 cells, and, concomitantly,

Tissue regeneration: intriguing roles for retinoids and a key role for ALDH1a2

Mammals can regenerate their tissues/organs to only a very limited extent, with the exception of the liver. However, some other vertebrate organisms can readily regenerate many different body parts. Because tissue regeneration and tissue repair show major mechanistic overlap in terms of genomic responses and both processes involve cell differentiation, it is not surprising that retinoids, both endogenously derived and externally added, have some fascinating effects on regeneration. Since the

Vitamin A and the heart: regulation of cell differentiation

After injury to the zebrafish heart cardiomyocytes proliferate at the wound site and the heart regenerates. ALDH1a2 induction by both the endocardium, an endothelial cell layer that lines the inside of the cardiac chambers, and the epicardium, a mesothelial layer that surrounds the cardiac chambers, is required for heart regeneration after trauma or tissue injury in zebrafish. Furthermore, the induction of ALDH1a2 generates local RA [53], [54], [55] (Fig. 3). LPS injection can also induce

Vitamin A and organ regeneration

During kidney regeneration many genes involved in kidney organogenesis are reactivated. In zebrafish, inhibition of histone deacetylase (HDAC) activity in combination with RA expanded the renal progenitor cell population. These results suggest that HDAC, RA, and the renal progenitor cells are mechanistically in the same signaling pathway [57]. Moreover, in the kidney ALDH1a2 was dramatically upregulated in podocytes in puromycin aminonucleoside-induced nephrosis (pan-nephrosis), suggesting that

RA stimulates the differentiation of podocytes and reduces HIV-associated nephropathy

Retinol deficiency during development is associated with renal abnormalities and malformations [68]. During kidney development stromal cells require retinol-mediated signals to control Ret expression in the ureteric bud [68]. RA is also involved in patterning early nephron progenitor cells in zebrafish nephrogenesis [69].

Human immunodeficiency (HIV) disease is associated with a nephropathy in which the podocytes, epithelial cells in the Bowman's capsule in the kidneys that wrap around the

Retinoic acid and retinoic acid receptors play a major role in the alveoli of the lung

The lung primordium forms from the primitive foregut during development and this process requires endogenously generated retinoic acid [77], but retinoids also play key roles in the formation and continued functioning of lung alveoli. Alveoli contain three major epithelial cell types. Type I epithelial cells carry out gas exchange, while type II epithelial cells make surfactant and can regenerate alveolar epithelium following injury. Type III epithelial cells may function as chemoreceptors.

Hox genes are key mediators of cell memory in the adult during tissue differentiation/regeneration

The examples above demonstrate the actions of endogenous and exogenous retinoids in adult animals in influencing the process of cell differentiation, but what are the molecular signaling pathways controlled by the RARs during the differentiation of adult stem cells? Hox (homeobox) genes encode transcription factors that regulate major aspects of differentiation in adult tissues, and the expression of these genes is known to regulate positional identity in the developing embryo [103]. Most of

Acknowledgements

I would like to thank Ms. Tamara Weissman and Ms. Lissett Checo for editorial assistance, Dr. John Wagner and Ms. Megan Ricard for critically reading this manuscript, and NIH grants NIAAA R01 AA018332, NIDCR R01 DE010389, and NCI R01 CA043796 for support.

References (127)

  • I.I. Ivanov et al.

    The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells

    Cell

    (2006)
  • E.J. Villablanca et al.

    MyD88 and retinoic acid signaling pathways interact to modulate gastrointestinal activities of dendritic cells

    Gastroenterology

    (2011)
  • E. Jaensson-Gyllenback et al.

    Bile retinoids imprint intestinal CD103(+) dendritic cells with the ability to generate gut-tropic T cells

    Mucosal Immunol.

    (2011)
  • R.A. Radu et al.

    Complement system dysregulation and inflammation in the retinal pigment epithelium of a mouse model for Stargardt macular degeneration

    J. Biol. Chem.

    (2011)
  • H. Sun et al.

    Retinal stimulates ATP hydrolysis by purified and reconstituted ABCR, the photoreceptor-specific ATP-binding cassette transporter responsible for Stargardt disease

    J. Biol. Chem.

    (1999)
  • A.C. Ross et al.

    Vitamin A and retinoic acid in the regulation of B-cell development and antibody production

    Vitam. Horm.

    (2011)
  • M. Kimura et al.

    Acyclic retinoid NIK-333 accelerates liver regeneration and lowers serum transaminase activities in 70% partially hepatectomized rats, in vivo

    Eur. J. Pharmacol.

    (2010)
  • L.K. Mathew et al.

    Comparative expression profiling reveals an essential role for raldh2 in epimorphic regeneration

    J. Biol. Chem.

    (2009)
  • K. Kikuchi et al.

    Retinoic acid production by endocardium and epicardium is an injury response essential for zebrafish heart regeneration

    Dev. Cell

    (2011)
  • A. Lepilina et al.

    A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration

    Cell

    (2006)
  • I. Stuckmann et al.

    Erythropoietin and retinoic acid, secreted from the epicardium, are required for cardiac myocyte proliferation

    Dev. Biol.

    (2003)
  • S. van Neerven et al.

    Inflammatory cytokine release of astrocytes in vitro is reduced by all-trans retinoic acid

    J. Neuroimmunol.

    (2010)
  • M. Agudo et al.

    A retinoic acid receptor beta agonist (CD2019) overcomes inhibition of axonal outgrowth via phosphoinositide 3-kinase signalling in the injured adult spinal cord

    Neurobiol. Dis.

    (2010)
  • G. Donmez et al.

    SIRT1 suppresses beta-amyloid production by activating the alpha-secretase gene ADAM10

    Cell

    (2010)
  • L. Barisoni et al.

    HIV-1 induces renal epithelial dedifferentiation in a transgenic model of HIV-associated nephropathy

    Kidney Int.

    (2000)
  • K.K. Ratnam et al.

    Role of the retinoic acid receptor-alpha in HIV-associated nephropathy

    Kidney Int.

    (2011)
  • L. Liu et al.

    Disruption of the lecithin:retinol acyltransferase gene makes mice more susceptible to vitamin A deficiency

    J. Biol. Chem.

    (2005)
  • S.M. O'Byrne et al.

    Retinoid absorption and storage is impaired in mice lacking lecithin:retinol acyltransferase (LRAT)

    J. Biol. Chem.

    (2005)
  • L. Wu et al.

    Acidic retinoids synergize with vitamin A to enhance retinol uptake and STRA6, LRAT, and CYP26B1 expression in neonatal lung

    J. Lipid Res.

    (2010)
  • T.J. Desai et al.

    Distinct roles for retinoic acid receptors alpha and beta in early lung morphogenesis

    Dev. Biol.

    (2006)
  • C. Wongtrakool et al.

    Down-regulation of retinoic acid receptor alpha signaling is required for sacculation and type I cell formation in the developing lung

    J. Biol. Chem.

    (2003)
  • J. Tepper et al.

    Can retinoic acid ameliorate the physiologic and morphologic effects of elastase instillation in the rat?

    Chest

    (2000)
  • M.D. Roth et al.

    Feasibility of retinoids for the treatment of emphysema study

    Chest

    (2006)
  • N. Fujino et al.

    Isolation of alveolar epithelial type II progenitor cells from adult human lungs

    Lab. Invest.

    (2011)
  • C.F. Kim et al.

    Identification of bronchioalveolar stem cells in normal lung and lung cancer

    Cell

    (2005)
  • R. Wang et al.

    Smoking-induced upregulation of AKR1B10 expression in the airway epithelium of healthy individuals

    Chest

    (2010)
  • L.J. Gudas et al.

    Retinoids regulate stem cell differentiation

    J. Cell. Physiol.

    (2011)
  • A.L. Means et al.

    The roles of retinoids in vertebrate development

    Annu. Rev. Biochem.

    (1995)
  • N. Chassaing et al.

    Phenotypic spectrum of STRA6 mutations: from Matthew–Wood syndrome to non-lethal anophthalmia

    Hum. Mutat.

    (2009)
  • T.J. Cunningham et al.

    Rdh10 mutants deficient in limb field retinoic acid signaling exhibit normal limb patterning but display interdigital webbing

    Dev. Dyn.

    (2011)
  • D.N. D'Ambrosio et al.

    Vitamin A metabolism: an update

    Nutrients

    (2011)
  • S. Kumar, L.L. Sandell, P.A. Trainor, F. Koentgen, G. Duester, Alcohol and aldehyde dehydrogenases: retinoid metabolic...
  • H.R. Hudlebusch et al.

    MMSET is highly expressed and associated with aggressiveness in neuroblastoma

    Cancer Res.

    (2011)
  • D. Subramanyam et al.

    PML-RAR{alpha} and Dnmt3a1 cooperate in vivo to promote acute promyelocytic leukemia

    Cancer Res.

    (2010)
  • X.H. Tang et al.

    Retinoids, retinoic acid receptors, and cancer

    Annu. Rev. Pathol.

    (2011)
  • J.L. Coombes et al.

    A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism

    J. Exp. Med.

    (2007)
  • L.M. Williams et al.

    Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3

    Nat. Immunol.

    (2007)
  • D. Mucida et al.

    Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid

    Science

    (2007)
  • T. Feng et al.

    Generation of mucosal dendritic cells from bone marrow reveals a critical role of retinoic acid

    J. Immunol.

    (2010)
  • G. Boschetti et al.

    Therapy with anti-TNFalpha antibody enhances number and function of Foxp3(+) regulatory T cells in inflammatory bowel diseases

    Inflamm. Bowel Dis.

    (2011)
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    This article is part of a Special Issue entitled Retinoid and Lipid Metabolism.

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