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

School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.
Stem cell reviews (Impact Factor: 3.21). 03/2010; 7(1):53-63. DOI: 10.1007/s12015-010-9146-1
Source: PubMed

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.

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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). "
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