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

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.

Figure 1. Major pathways of retinol (vitamin A) metabolism in mammalian cells

Not all of these enzymatic pathways are present in all cells; Stra6 is a receptor for RBP4 (serum retinol-binding protein), and both Stra6 and lecithin:retinol acyltransferase (LRAT) are required for accumulation of retinol within some, but not all cell types. RARE, DNA retinoic acid response element; RAR, retinoic acid receptor; RXR, retinoid X receptor; ADHs, alcohol dehydrogenases; ALDH, aldehyde dehydrogenase; CRBP1, cellular retinol binding protein 1; CRABP1, 2, cellular retinoic acid-binding proteins 1 and 2. Rol, retinol; Ral, retinaldehyde; RA, all-trans retinoic acid (modified from [3]).

FIGURE 2. “Multiple-step model” for RA-mediated mucosal DC generation

One mechanism for T_reg production: mucosal DC precursors (pre-DCs) encounter RA, which is metabolized by ALDH⁺ bone marrow cells from dietary vitamin A, in a bone marrow microenvironment. RA induces pre-DCs to express CCR9 and ALDH1a2, and suppresses SOCS3 while enhancing STAT3 activation. CCR9⁺ DCs then exit the bone marrow and migrate into the intestine by the chemotactic attraction of CCR9 ligand CCL25. In the intestinal mucosa, commensal TLR (toll-like receptor) ligands and epithelial cell-derived signals further instruct DCs to develop into fully functional “regulatory” mucosal DCs, which are competent to promote the maturation of Foxp3⁺ Tregs. In contrast, without RA conditioning, pre-DCs develop into “inflammatory” DCs, which produce proinflammatory cytokines in response to TLR7 signals and promote Th1 and Th17 cell differentiation [22].

Figure 3. Model: ALDH1a2 is necessary but not sufficient for regeneration following injury

Depiction of the hypothesis that regeneration occurs only after ALDH1a2 induction.

Figure 4. Hox status and bone regeneration in mouse

Cells expressing Hox genes (for example Hoxa11) are in light blue and those not expressing Hox are indicated in light grey. Hox(+) skeletal stem cells can only heal orthotopic Hox(+) bone injury site (tibia). (a) Hox(+) skeletal stem cells cannot repair a Hox null injury site (mandible). (b) Conversely, Hox null skeletal stem cells will express the ectopic Hox gene when transplanted into a Hox(+) injury site and regenerate the ectopic bone [103].