Transgenic Overexpression of Hepatocyte Growth Factor in the β-Cell Markedly Improves Islet Function and Islet Transplant Outcomes in Mice

Garcı́a-Ocaña, Adolfo; Vasavada, Rupangi C.; Cebrián, Ana; Reddy, Varun; Takane, Karen K.; López-Talavera, Juan-Carlos; Stewart, Andrew F.

doi:10.2337/diabetes.50.12.2752

Cited by 149 publications

(173 citation statements)

References 45 publications

(61 reference statements)

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“…Previous studies showed that activin A, betacellulin, hepatocyte growth factor, and VEGF could induce differentiation of pancreatic ␤ cells (29)(30)(31). Culture of E17.5 intestinal epithelial cells with such molecules, however, leads only to very low expression of the insulin gene compared with GLP-1-(1-37) (Fig.…”

Section: Insulin Induction In Intestinal Epithelial Cells Is Due To Amentioning

confidence: 99%

Glucagon-like peptide 1 (1–37) converts intestinal epithelial cells into insulin-producing cells

Suzuki

Nakauchi

Taniguchi

2003

Proc. Natl. Acad. Sci. U.S.A.

127

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Glucagon-like peptide (GLP) 1 is produced through posttranslational processing of proglucagon and acts as a regulator of various homeostatic events. Among its analogs, however, the function of GLP-1-(1-37), synthesized in small amounts in the pancreas, has been unclear. Here, we find that GLP-1-(1-37) induces insulin production in developing and, to a lesser extent, adult intestinal epithelial cells in vitro and in vivo, a process mediated by upregulation of the Notch-related gene ngn3 and its downstream targets, which are involved in pancreatic endocrine differentiation. These cells became responsive to glucose challenge in vitro and reverse insulin-dependent diabetes after implantation into diabetic mice. Our findings suggest that efficient induction of insulin production in intestinal epithelial cells by GLP-1-(1-37) could represent a new therapeutic approach to diabetes mellitus.A t the end of gastrulation, the mouse endoderm exists as a one-cell layer covering the mesoderm and ectoderm of the embryo. Gut development begins with the invagination of the most anterior and posterior endoderm at embryonic day 8.5 (E8.5), leading to the formation of two open-ended tubes. This anterior and posterior migration, in combination with embryonic twisting, closes the midgut and forms a primitive gut tube. Pseudostratified immature epithelium is found in the gut by E15, and subsequent remodeling of the gut endoderm between E15 and E19 leads to the production of nascent villi with a monolayer of epithelial cells. During the first 2 postnatal wk, the intervillus epithelium develops into crypts, which contain a dividing epithelial stem cell population. Crypt cell progenies differentiate into the nonproliferative four principal epithelial cell lineages: enterocytes (columnar cells), goblet cells, enteroendocrine cells, and Paneth cells (1).Generation of these cell types requires a number of processes regulated by various signaling molecules and transcription factors. Like neuronal development in the central nervous system, the Notch signaling pathway is involved in endodermal endocrine differentiation (2-5). In this signaling system, ligands bind to Notch receptors and activate their intracellular domains, leading to interaction with the DNA-binding protein RBP-J k . This protein in turn activates expression of the basic helix-loophelix Hes genes (6, 7), which, in turn, repress expression of downstream target genes, including neurogenin (ngn) and Math-1 (8, 9). Decreased Hes repression results in cell differentiation to a primary fate. In the developing pancreases of mice lacking RBP-J k or a Notch ligand, Delta-like gene 1 (Dll1), differentiation of pancreatic endocrine cells was accelerated (10, 11). Overexpression of ngn3 or the intracellular domain of Notch3 (a repressor of Notch signaling) (12) also resulted in a similar pancreatic phenotype (2). Deletion of Hes-1 leads to pancreatic hypoplasia caused by increased endocrine differentiation from pancreatic progenitors and to abnormal endocrine differentiation of the stoma...

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Section: Insulin Induction In Intestinal Epithelial Cells Is Due To Amentioning

confidence: 99%

Glucagon-like peptide 1 (1–37) converts intestinal epithelial cells into insulin-producing cells

Suzuki

Nakauchi

Taniguchi

2003

Proc. Natl. Acad. Sci. U.S.A.

127

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“…that HGF is an insulinotropic factor for adult islet β cells and is able to induce insulin expression in non-β cells [14]. Nicotinamide, in combination with EGF and HGF, resulted in increase in the numbers of islets in in vitro culture of islet progenitor cells [13].…”

Section: Disscussionmentioning

confidence: 98%

In vitro cultivation and differentiation of fetal liver stem cells from mice

Feng

Guo

2005

Cell Res

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During embryonic development, pluripotent endoderm tissue in the developing foregut may adopt pancreatic fate or hepatic fate depending on the activation of key developmental regulators. Transdifferentiation occurs between hepatocytes and pancreatic cells under specific conditions. Hepatocytes and pancreatic cells have the common endodermal progenitor cells. In this study we isolated hepatic stem/progenitor cells from embryonic day (ED) 12-14 Kun-Ming mice with fluorescence-activated cell sorting (FACS). The cells were cultured under specific conditions. The cultured cells deploy dithizone staining and immunocytochemical staining at the 15th, 30th and 40th day after isolation. The results indicated the presence of insulin-producing cells. When the insulin-producing cells were transplanted into alloxaninduced diabetic mice, the nonfasting blood glucose level was reduced. These results suggested that fetal liver stem/ progenitor cells could be converted into insulin-producing cells under specific culture conditions. Fetal liver stem/ progenitor cells could become the potential source of insulin-producing cells for successful cell transplantation therapy strategies of diabetes.

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“…(Miettinen et al 2000). Hepatocyte Growth Factor (Hgf) also appears important for growth and differentiation of the pancreas (Garcia-Ocana et al 2001) and plays an important role in postnatal insulin secretion via the Hgf receptor (c-met) (Roccisana et al 2005).…”

Section: Pancreatic Growth Endocrine Specification and Islet Cell DImentioning

confidence: 99%

Embryonic stem cells to beta-cells by understanding pancreas development

Best¹,

Carroll²,

Hanley³

et al. 2008

Molecular and Cellular Endocrinology

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Please cite this article as: Best, M., Carroll, M., Hanley, N.A., Hanley, K.P., Embryonic stem cells to beta-cells by understanding pancreas development, Molecular and Cellular Endocrinology (2007), doi:10.1016/j.mce.2008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Transgenic Overexpression of Hepatocyte Growth Factor in the β-Cell Markedly Improves Islet Function and Islet Transplant Outcomes in Mice

Cited by 149 publications

References 45 publications

Glucagon-like peptide 1 (1–37) converts intestinal epithelial cells into insulin-producing cells

Glucagon-like peptide 1 (1–37) converts intestinal epithelial cells into insulin-producing cells

In vitro cultivation and differentiation of fetal liver stem cells from mice

Embryonic stem cells to beta-cells by understanding pancreas development

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