Vitamin D and Vitamin A Receptor Expression and the Proliferative Effects of Ligand Activation of These Receptors on the Development of Pancreatic Progenitor Cells Derived from Human Fetal Pancreas
ABSTRACT The growth and development of pancreatic islet cells are regulated by various morphogens. Vitamin A modulates in vitro differentiation of islet cells and vitamin D affects beta-cell insulin secretion, while both vitamin ligands act through heterodimerization with the retinoid X receptor (RXR). However, their effects in modulating pancreatic development have not been determined. In this study, cultured human pancreatic progenitor cells (PPCs) isolated from human fetal pancreas were stimulated to differentiate into islet-like cell clusters (ICCs). RT-PCR, Western blotting and immunocytochemistry were used to examine the expression and localization of vitamin D receptor (VDR), retinoic acid receptor (RAR), and RXR in PPCs. The effects of added all-trans retinoic acid (atRA, a form of vitamin A), calcitriol (activated vitamin D) and of these ligands together on PPC cell viability, proliferation and apoptosis were assessed by MTT, BrdU and ELISA assays, respectively. Post-treatment neurogenin-3 (NGN3) expression, necessary for islet-cell lineage development, was examined by real-time RT-PCR. Results showed that RAR, RXR and VDR were expressed in PPCs. RAR and RXR were localized in nuclei, and the VDR in nuclei, cytoplasm and plasma membrane. atRA and calcitriol each increased PPC viability and proliferation; atRA additionally decreased PPC apoptosis. Co-addition of atRA and calcitriol had no additive effects on cell viability but did increase ngn3 responses. In conclusion, RAR, RXR and VDR are expressed in human fetal PPCs and PPC proliferation can be promoted by calcitriol, atRA or both together, data valuable for elucidating mechanisms underlying islet development and for developing clinical islet transplantation.
- SourceAvailable from: Jose M González-Sancho
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- "Titration out of common co-activators, but not of RXR, may be the mechanism by which ligand-bound VDR represses retinoic acid receptor (RAR) transactivation in GH4C1 pituitary cells (Jiménez-Lara and Aranda, 1999). The relation between 1α,25(OH) 2 D 3 and retinoic acid is however complex, as cooperative effects on target genes and cellular outcome (proliferation inhibition and differentiation) have been described in other systems (Tavera-Mendoza et al., 2006; Anand et al., 2008; Ng et al., 2010). As for estrogen receptor (ER), D. Feldman's group has shown that 1α,25(OH) 2 D 3 exerts a multilevel protective effect against breast cancer that includes the inhibition of estrogen synthesis through the direct and indirect repression of aromatase (CYP19) and the downregulation of ER-α expression through two VDREs in its promoter region (Krishnan et al., 2010; Swami et al., 2013). "
ABSTRACT: Many studies in different biological systems have revealed that 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) modulates signaling pathways triggered at the plasma membrane by agents such as Wnt, transforming growth factor (TGF)-β, epidermal growth factor (EGF), and others. In addition, 1α,25(OH)2D3 may affect gene expression by paracrine mechanisms that involve the regulation of cytokine or growth factor secretion by neighboring cells. Moreover, post-transcriptional and post-translational effects of 1α,25(OH)2D3 add to or overlap with its classical modulation of gene transcription rate. Together, these findings show that vitamin D receptor (VDR) cannot be considered only as a nuclear-acting, ligand-modulated transcription factor that binds to and controls the transcription of target genes. Instead, available data support the view that much of the complex biological activity of 1α,25(OH)2D3 resides in its capacity to interact with membrane-based signaling pathways and to modulate the expression and secretion of paracrine factors. Therefore, we propose that future research in the vitamin D field should focus on the interplay between 1α,25(OH)2D3 and agents that act at the plasma membrane, and on the analysis of intercellular communication. Global analyses such as RNA-Seq, transcriptomic arrays, and genome-wide ChIP are expected to dissect the interactions at the gene and molecular levels.Frontiers in Physiology 02/2014; 5:60. DOI:10.3389/fphys.2014.00060 · 3.50 Impact Factor
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ABSTRACT: IntroductionInadequate intake of minerals and vitamins during growth has become a major health problem in developed and developing countries, particularly in pregnant women, infants and children who have an unbalanced diet.Methods Studies in humans and animals have shown that micronutrient deficiency during development may be responsible for in utero programming of cardiovascular and renal diseases in adulthood, such as obesity, diabetes and hypertension. Among the mechanisms involved are epigenetic changes, alteration in organogenesis, apoptotic remodelling processes and metabolic and hormonal alterations.ResultsThis work is an updated review of the association between micronutrient deficiencies during foetal and post-natal life, the development of cardiovascular disease in adulthood, and the alterations observed in these.Conclusions The benefits of micronutrient supplementation during pregnancy are discussed.Clínica e Investigación en Arteriosclerosis 03/2012; 24(2):71–81. DOI:10.1016/j.arteri.2012.01.004
Article: Geocities (A) and (B)Journal of Interactive Marketing 01/2000; 14(1):60-72. DOI:10.1002/(SICI)1520-6653(200024)14:13.0.CO;2-A · 1.68 Impact Factor