Summary
The transcription factor Neurogenin3 (Ngn3) is required for islet-cell type specification. Here, we show that hepatic gene transfer of Ngn3 transiently induces insulin in terminally-differentiated hepatocytes but fails to transdifferentiate them, i.e. switch their lineage into islet cells. However, Ngn3 leads to long-term diabetes reversal in mice due to the emergence of periportal islet-like cell clusters. These neo-islets display glycemia-regulated insulin, β-cell-specific transcripts, and an islet-specific transcription cascade, and produce all four major islet hormones. They appear to arise from hepatic progenitor cells, most likely endoderm-derived oval cells. Thus, transfer of a single lineage-defining transcription factor, Ngn3, is sufficient to induce cell-lineage switching from hepatic to an islet lineage in these progenitor cells, a process consistent with transdetermination, i.e, lineage switching in lineage-determined, but not terminally-differentiated cells. This paradigm of induced transdetermination of receptive progenitor cells in vivo may be generally applicable to therapeutic organogenesis for multiple diseases including diabetes.
Our study has identified a unique mechanism that describes how components of pathogens common in the urinary system may contribute to the malignant transformation of benign prostate epithelia.
Transforming growth factor (TGF)-B is a potent immunosuppressant. Overproduction of TGF-B by tumor cells may lead to tumor evasion from the host immune surveillance and tumor progression. The present study was conducted to develop a treatment strategy through adoptive transfer of tumor-reactive TGF-B-insensitive CD8 + + T cells. The mouse TRAMP-C2 prostate cancer cells produced large amounts of TGF-B1 and were used as an experimental model. C57BL/6 mice were primed with irradiated TRAMP-C2 cells. CD8 + + T cells were isolated from the spleen of primed animals, were expanded ex vivo, and were rendered TGF-B insensitive by infecting with a retrovirus containing dominant-negative TGF-B type II receptor. Results of in vitro cytotoxic assay revealed that these CD8 + T cells showed a specific and robust tumor-killing activity against TRAMP-C2 cells but were ineffective against an irrelevant tumor line, B16-F10. To determine the in vivo antitumor activity, recipient mice were challenged with a single injection of TRAMP-C2 cells for a period up to 21 days before adoptive transfer of CD8 + + T cells was done. Pulmonary metastasis was either eliminated or significantly reduced in the group receiving adoptive transfer of tumor-reactive TGF-B-insensitive CD8 + + T cells. Results of immunofluorescent studies showed that only tumor-reactive TGF-B-insensitive CD8 + + T cells were able to infiltrate into the tumor and mediate apoptosis in tumor cells. Furthermore, transferred tumor-reactive TGF-B-insensitive CD8 + + T cells were able to persist in tumor-bearing hosts but declined in tumor-free animals. These results suggest that adoptive transfer of tumor-reactive TGF-B-insensitive CD8 + + T cells may warrant consideration for cancer therapy.
The peripheral induction of T regulatory cells can be accomplished by TGF-β through an epigenetic regulation leading to the expression of Foxp3. However, the exact mechanism of such a TGF-β-mediated action remains unclear. In the current study, we found that TGF-β treatment of CD4+CD25− T cells during T cell activation led to a transient inhibition of the phosphorylation of ERK followed by the induction of Foxp3 expression in these cells. Direct treatment with a specific ERK inhibitor, UO126, during CD4+CD25− T cell activation also induced Foxp3 expression and conferred a suppressive function to the induced Foxp3+ T cells. Furthermore, treatment of T cells with either TGF-β or UO126 significantly down-regulated the expression of DNMTs, a reaction normally elicited by demethylation agents, such as 5-Aza-2′-deoxycytidine. These results indicate that the epigenetic regulation of TGF-β-induced expression of Foxp3 may be mediated through the inactivation of ERK.
The energy- and fat-dense CF diet is primarily achieved by overconsumption of EDNP foods, rather than ND sources. This dietary pattern may not be optimal for the future health of children with CF, who are now expected to survive well into adulthood.
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