Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewEmerging roles for retinoids in regeneration and differentiation in normal and disease states☆
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.
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This article is part of a Special Issue entitled Retinoid and Lipid Metabolism.