Multi-drug resistance is an important element which leads to ineffectiveness of chemotherapeutics. To identify subpopulations of cancerous prostate cells with multi-drug resistance and cancer stem-cell properties has recently become a major research interest. We identified a subpopulation from the prostate cancer cell line 22RV1, which have high surface expression of both CD117 and ABCG2. We found this subpopulation of cells termed CD117(+)/ABCG2(+) also overexpress stem cells markers such as Nanog, Oct4, Sox2, Nestin, and CD133. These cells are highly prolific and are also resistant to treatment with a variety of chemotherapeutics such as casplatin, paclitaxel, adriamycin, and methotrexate. In addition, CD117(+)/ABCG2(+) cells can readily establish tumors in vivo in a relatively short time. To investigate the mechanism of aggressive tumor growth and drug resistance, we examined the CpG islands on the ABCG2 promoter of CD117(+)/ABCG2(+) cells and found they were remarkably hypomethylated. Furthermore, chromatin immunoprecipitation assays revealed high levels of both histone 3 acetylation and H3K4 trimethylation at the CpG islands on the ABCG2 promoter. Our these data suggest that CD117(+)/ABCG2(+) cells could be reliably sorted from the human prostate cancer cell line 22RV1, and represent a valuable model for studying cancer cell physiology and multi-drug resistance. Furthermore, identification and study of these cells could have a profound impact on selection of individual treatment strategies, clinical outcome, and the design or selection of the next generation of chemotherapeutic agents.
Human amniotic epithelial cells (hAECs), having the characteristics of both embryonic and pluripotent stem cells, have the potential to differentiate into various cells. A good deal of research has explored the clinical therapeutic potential of hAECs; rat amniotic epithelial cells have been reported to ameliorate functional deficits after stroke in rats, likely due to neuronal differentiation and cytokine secretion by these cells. We isolated hAECs and transfected them with glial cell line-derived neurotrophic factor (GDNF) or enhanced green fluorescent protein (EGFP) gene using lentiviral vectors. These cells were then transplanted into the brains of rats subjected to a transient middle cerebral artery occlusion. The hAECs survived and migrated to the ischemic area of rats, and some of the transplanted hAECs expressed the neuronal marker MAP2 and the neuronal progenitor marker Nestin, together with the astrocyte marker glial fibrillary acidic protein, and hAEC-EGFP can significantly ameliorate behavioral dysfunction and reduce infarct volume of ischemic rats. By transfecting the cells with lentiviral vectors, GDNF can be stably overexpressed in hAECs, and hAEC-GDNF can more rapidly rescue the deficits of rats after middle cerebral artery occlusion compared with hAEC-EGFP-treated rats. Moreover, the nontransduced cells also had effects comparable to the GDNF-transduced cells on caspase-3 and lesion volume. Because hAECs are in unlimited supply, and their use is not encumbered by ethical arguments, hAECs have a great advantage for stem cell therapy. This model holds tremendous potential for development into wide use in cell-mediated gene therapy in the future.
The development of a technique to induce the transformation of somatic cells to a pluripotent state via the ectopic expression of defined transcription factors was a transformational event in the field of regenerative medicine. The development of this technique also impacted ophthalmology, as patient-specific induced pluripotent stemcells (iPSCs) may be useful resources for some ophthalmological diseases. The lens is a key refractive element in the eye that focuses images of the visual world onto the retina. To establish a new model for drug screening to treat lens diseases and investigating lens aging and development, we examined whether human lens epithelial cells (HLECs) could be induced into iPSCs and if lens-specific differentiation of these cells could be achieved under defined chemical conditions. We first efficiently reprogrammed HLECs from age-related cataract patients to iPSCs with OCT-4, SOX-2, and KLF-4. The resulting HLEC-derived iPS (HLE-iPS) colonies were indistinguishable from human ES cells with respect to morphology, gene expression, pluripotent marker expression and their ability to generate all embryonic germ-cell layers. Next, we performed a 3-step induction procedure: HLE-iPS cells were differentiated into large numbers of lens progenitor-like cells with defined factors (Noggin, BMP and FGF2), and we determined that these cells expressed lens-specific markers (PAX6, SOX2, SIX3, CRYAB, CRYAA, BFSP1, and MIP). In addition, HLE-iPS-derived lens cells exhibited reduced expression of epithelial mesenchymal transition (EMT) markers compared with human embryonic stem cells (hESCs) and fibroblast-derived iPSCs. Our study describes a highly efficient procedure for generating lens progenitor cells from cataract patient HLEC-derived iPSCs. These patient-derived pluripotent cells provide a valuable model for studying the developmental and molecular biological mechanisms that underlie cell determination in lens development and cataract pathophysiology.
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