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PAX4 Gene Transfer Induces ?-to-? Cell Phenotypic Conversion and Confers Therapeutic Benefits for Diabetes Treatment.

ABSTRACT: The transcription factor Pax4 plays a critical role in the determination of ?- versus ?-cell lineage during endocrine pancreas development. In this study, we explored whether Pax4 gene transfer into ?-cells could convert them into functional ?-cells and thus provide therapeutic benefits for insulin-deficient diabetes. We found that Pax4 delivered by adenoviral vector, Ad5.Pax4, induced insulin expression and reduced glucagon expression in ?TC1.9 cells. More importantly, these cells exhibited glucose-stimulated insulin secretion, a key feature of functional ?-cells. When injected into streptozotocin-induced diabetic mice, Pax4-treated ?TC1.9 cells significantly reduced blood glucose, and the mice showed better glucose tolerance, supporting that Pax4 gene transfer into ?TC1.9 cells resulted in the formation of functional ?-cells. Furthermore, treatment of primary human islets with Ad5.Pax4 resulted in significantly improved ?-cell function. Detection of glucagon(+)/Pax4(+)/Insulin(+) cells argued for Pax4-induced ?-to-? cell transitioning. This was further supported by quantification of glucagon and insulin bi-hormonal cells, which was significantly higher in Pax4-treated islets than in controls. Finally, direct administration of Ad5.Pax4 into the pancreas of insulin-deficient mice ameliorated hyperglycemia. Taken together, our data demonstrate that manipulating Pax4 gene expression represents a viable therapeutic strategy for the treatment of insulin deficient diabetes.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC4817809 | biostudies-other | 2016 Feb

REPOSITORIES: biostudies-other

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PAX4 Gene Transfer Induces α-to-β Cell Phenotypic Conversion and Confers Therapeutic Benefits for Diabetes Treatment.

Zhang Yanqing Y Fava Genevieve E GE Wang Hongjun H Mauvais-Jarvis Franck F Fonseca Vivian A VA Wu Hongju H

Molecular therapy : the journal of the American Society of Gene Therapy 20151005 2

The transcription factor Pax4 plays a critical role in the determination of α- versus β-cell lineage during endocrine pancreas development. In this study, we explored whether Pax4 gene transfer into α-cells could convert them into functional β-cells and thus provide therapeutic benefits for insulin-deficient diabetes. We found that Pax4 delivered by adenoviral vector, Ad5.Pax4, induced insulin expression and reduced glucagon expression in αTC1.9 cells. More importantly, these cells exhibited glu ...[more]

PMID: 26435408

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Project description:Machado-Joseph disease (MJD) is a fatal neurodegenerative disease caused by expansion of the trinucleotide repeat region within the ATXN3/MJD gene. Mutation of ATXN3 causes formation of neurotoxic ataxin-3 protein aggregates, neurodegeneration and motor deficits. Here we investigated the therapeutic potential and mechanistic activity of sodium butyrate (SB), the sodium salt of butyric acid, a metabolite naturally produced by gut microbiota, on cultured SH-SY5Y cells and transgenic zebrafish expressing human ataxin-3 containing 84 glutamine (Q) residues to model MJD. MJD SH-SY5Y cells were found to contain ataxin-3 oligomeric species and protein aggregates. Treatment with SB increased activity of the autophagy protein quality control pathway in the MJD cells, decreased presence of ataxin-3 aggregates and presence of ataxin-3 oligomers in an autophagy-dependent manner. Treatment with SB was also beneficial in vivo, improving swimming performance, increasing autophagy activity and decreasing presence of insoluble ataxin-3 protein species in the transgenic MJD zebrafish. Co-treating the MJD zebrafish with SB and chloroquine, an autophagy inhibitor, prevented the beneficial effects of SB on the zebrafish swimming, suggesting that the improved swimming performance was autophagy-dependent. To identify mechanism of the induction of autophagy by SB, we performed proteomic analysis of protein lysates from the SB treated and untreated MJD SH-SY5Y cells. We found that SB treatment had increased activity of Protein Kinase A and AMPK signaling. Immunoblot analysis confirmed that SB treatment had increased levels of acetylated FOXO1 protein. Further, co-treatment with an inhibitor of FOXO1 transcriptional activity (AS1842856) prevented the increase in autophagosome formation (LC3II/I) usually produced by SB treatment. Together our findings indicate that treatment with SB can increase activity of the autophagy pathway through a FOXO1-dependent process and that this has beneficial effects in vitro and in vivo. We propose that treatment with sodium butyrate warrants further investigation for the treatment of neurodegenerative diseases underpinned by proteinopathy mechanisms, including MJD.

Dataset Information

PAX4 Gene Transfer Induces ?-to-? Cell Phenotypic Conversion and Confers Therapeutic Benefits for Diabetes Treatment.

Publications

PAX4 Gene Transfer Induces α-to-β Cell Phenotypic Conversion and Confers Therapeutic Benefits for Diabetes Treatment.

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