Molecular characterization of a toxicological tipping point in human induced pluripotent stem cell (hiPSC)-derived endoderm exposed to all-trans retinoic acid (ATRA)
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ABSTRACT:
PROVIDER: PRJNA545324 | ENA |
REPOSITORIES: ENA
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Project description:Embryonic development commences with the formation of three germ layers from the primitive streak during gastrulation. The endoderm layer gives rise to the gut tube, leading to development of several internal organs, including the thyroid, thymus, lungs, stomach, liver, pancreas, and intestines. We differentiated human induced pluripotent stem cells (hiPSCs) to embryonic endoderm and sought to identify a tipping point at which the developing system did not recover from perturbations caused by exposure to a known teratogen, all-trans retinoic acid (ATRA). Differentiating iPSC-derived endoderm was exposed to five concentrations of ATRA between 0.001 and 10 µM at 6h, 96h, or 192h and assessed for forkhead box A2 (FOXA2) protein expression and global gene transcript expression measured by RNA-sequencing. A tipping point of 17±11 nM was identified where patterns of differentially expressed genes supported a shift in the developmental trajectory away from embryonic endoderm in favor of mesoderm and extraembryonic endoderm.
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Project description:All-trans retinoic acid (ATRA) is a potent retinoid, which has been used successfully in different clinical settings as a potential drug to treat COPD and emphysema. In alveolar macrophages, ATRA selectively down-regulates MMP-9 and up-regulates TIMP-1 expression. In the present study, we analyzed additional genes modulated by ATRA by performing mRNA expression array on alveolar macrophages after treatment with ATRA.
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Project description:Retinoids have been used as potential chemotherapeutic or chemo-preventive agents because of their differentiation, anti-proliferative, pro-apoptotic, and anti-oxidant effects. We investigated the effect of all trans- retinoic acid (ATRA) at different stages of the neoplastic transformation using an in vitro model of breast cancer progression. This model was previously developed by treating the human normal-like breast epithelial MCF-10F cells with high dose of estradiol and consist of five cell lines which shown a progressive neoplastic transformation: MCF-10F (normal stage), trMCF (premalignant stage), bsMCF (invasive stage) and caMCF (tumorigenic stage). In 3D-cultures, MCF-10F cells form tubules resembling the normal mammary gland although after treatment with high doses of estradiol, trMCF cells, formed tubules and, spherical masses which are an indication of cell transformation. By ring cloning, trMCF clone 11 which only formed spherical masses in collagen was isolated. Our results showed that the early transformed trMCF clone 11 cells shown a reduction of spherical masses and increased of tubules in collagen after being treated with 10-5M (10µM) and 10-6M (1µM) ATRA; the number of tubules was higher in cells treated with 10-6M ATRA (43% vs. 10% tubules). The invasive bsMCF and tumorigenic caMCF cells did not shown any changes in morphology after ATRA treatment. Analysis of expression studies in early transformed cells treated with 10-6M ATRA showed that 271 probes upregulated in trMCF clone 11 cells were downregulated after ATRA treatment and, 316 probes that were downregulated were upregulated after ATRA treatment in these cells to similar levels than the normal breast epithelial cells MCF-10F. These genes were involved in the aryl hydrocarbon receptor signaling, RAR Activation, xenobiotic metabolisms signaling, molecular mechanisms of cancer and cell morphology. Our results shown that ATRA was able to re-differentiate transformed cells at early stages of the neoplastic process suggesting that ATRA could potentially be used to inhibit the progression of premalignant lesions of the breast such as ductal carcinoma in situ (DCIS).
2013-12-13 | GSE51549 | GEO
Project description:All-trans retinoic acid (ATRA) is a potent retinoid, which has been used successfully in different clinical settings as a potential drug to treat COPD and emphysema. In alveolar macrophages, ATRA selectively down-regulates MMP-9 and up-regulates TIMP-1 expression. In the present study, we analyzed additional genes modulated by ATRA by performing mRNA expression array on alveolar macrophages after treatment with ATRA. Total RNA was isolated from BAL cells cultivated either in the presence of liposomal ATRA or left untreated for 3 days. Total RNA from five independent donors were pooled at 0.4 µg each to give a final amount of 2µg. This pooled RNA was used for microarray analysis using the Affymatrix array
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Project description:Retinoids have been used as potential chemotherapeutic or chemo-preventive agents because of their differentiation, anti-proliferative, pro-apoptotic, and anti-oxidant effects. We investigated the effect of all trans- retinoic acid (ATRA) at different stages of the neoplastic transformation using an in vitro model of breast cancer progression. This model was previously developed by treating the human normal-like breast epithelial MCF-10F cells with high dose of estradiol and consist of five cell lines which shown a progressive neoplastic transformation: MCF-10F (normal stage), trMCF (premalignant stage), bsMCF (invasive stage) and caMCF (tumorigenic stage). In 3D-cultures, MCF-10F cells form tubules resembling the normal mammary gland although after treatment with high doses of estradiol, trMCF cells, formed tubules and, spherical masses which are an indication of cell transformation. By ring cloning, trMCF clone 11 which only formed spherical masses in collagen was isolated. Our results showed that the early transformed trMCF clone 11 cells shown a reduction of spherical masses and increased of tubules in collagen after being treated with 10-5M (10M-BM-5M) and 10-6M (1M-BM-5M) ATRA; the number of tubules was higher in cells treated with 10-6M ATRA (43% vs. 10% tubules). The invasive bsMCF and tumorigenic caMCF cells did not shown any changes in morphology after ATRA treatment. Analysis of expression studies in early transformed cells treated with 10-6M ATRA showed that 271 probes upregulated in trMCF clone 11 cells were downregulated after ATRA treatment and, 316 probes that were downregulated were upregulated after ATRA treatment in these cells to similar levels than the normal breast epithelial cells MCF-10F. These genes were involved in the aryl hydrocarbon receptor signaling, RAR Activation, xenobiotic metabolisms signaling, molecular mechanisms of cancer and cell morphology. Our results shown that ATRA was able to re-differentiate transformed cells at early stages of the neoplastic process suggesting that ATRA could potentially be used to inhibit the progression of premalignant lesions of the breast such as ductal carcinoma in situ (DCIS). We investigated the effect of all trans- retinoic acid (ATRA) at different stages of the neoplastic transformation using an in vitro model of breast cancer progression. This model was previously developed by treating the human normal-like breast epithelial MCF-10F cells with high dose of estradiol and consist of five cell lines which shown a progressive neoplastic transformation: MCF-10F (normal stage), trMCF (premalignant stage), bsMCF (invasive stage) and caMCF (tumorigenic stage).
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Project description:A role for vitamin A in host defense against Mycobacterium tuberculosis has been suggested through epidemiological and in vitro studies; however, the antimicrobial mechanism is unclear. Here, we demonstrate that vitamin A mediates host defense through regulation of cellular cholesterol content. Comparison of monocytes stimulated with all-trans retinoic acid (ATRA) or 1,25-dihydroxyvitamin D3, the biologically active forms of vitamin A and vitamin D respectively, indicates that ATRA and 1,25D3 induce mechanistically distinct antimicrobial activities. Gene expression profiling reveals that ATRA but not 1,25D3 triggers a lipid metabolism and efflux pathway, including expression of lysosomal lipid transport gene NPC2. ATRA-induced decrease in total cellular cholesterol content, subcellular lipid reorganization, lysosomal acidification and antimicrobial activity are all dependent upon expression of NPC2. Finally, the addition of HIV-protease inhibitors known to inhibit cholesterol efflux, Ritonavir and Nelfinavir, blocked both ATRA-induced cholesterol decrease as well as antimicrobial activity. Taken together, these results suggest that the vitamin A-mediated host defense mechanism against M. tuberculosis requires regulation of cellular cholesterol.
2013-12-31 | GSE46268 | GEO
Project description:A role for vitamin A in host defense against Mycobacterium tuberculosis has been suggested through epidemiological and in vitro studies; however, the antimicrobial mechanism is unclear. Here, we demonstrate that vitamin A mediates host defense through regulation of cellular cholesterol content. Comparison of monocytes stimulated with all-trans retinoic acid (ATRA) or 1,25-dihydroxyvitamin D3, the biologically active forms of vitamin A and vitamin D respectively, indicates that ATRA and 1,25D3 induce mechanistically distinct antimicrobial activities. Gene expression profiling reveals that ATRA but not 1,25D3 triggers a lipid metabolism and efflux pathway, including expression of lysosomal lipid transport gene NPC2. ATRA-induced decrease in total cellular cholesterol content, subcellular lipid reorganization, lysosomal acidification and antimicrobial activity are all dependent upon expression of NPC2. Finally, the addition of HIV-protease inhibitors known to inhibit cholesterol efflux, Ritonavir and Nelfinavir, blocked both ATRA-induced cholesterol decrease as well as antimicrobial activity. Taken together, these results suggest that the vitamin A-mediated host defense mechanism against M. tuberculosis requires regulation of cellular cholesterol. Monocytes derived from four independent healthy blood donors that were stimulated with control (CTRL), ATRA or 1,25D3 at 10-8M for 18 hours.
2013-12-31 | E-GEOD-46268 | biostudies-arrayexpress