Publications by authors named "Michelle A Guney"

8 Publications

  • Page 1 of 1

Pancreatic β cell regeneration: To β or not to β.

Curr Opin Physiol 2020 Apr 5;14:13-20. Epub 2019 Nov 5.

Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Center, Aurora CO 80045a.

Diabetes is a major worldwide health problem which results from the loss and/or dysfunction of pancreatic insulin-producing β cells in the pancreas. Therefore, there is great interest in understanding the endogenous capacity of β cells to regenerate under normal or pathological conditions, with the goal of restoring functional β cell mass in patients with diabetes. Here, we summarize the current status of β cell regeneration research, which has been broadly divided into three mechanisms: 1. proliferation of existing β cells; 2. neogenesis of β cells from adult ductal progenitors; and 3. transdifferentiation of other cell types into β cells. We discuss the evidence and controversies for each mechanism in mice and humans, as well as the prospect of using these approaches for the treatment of diabetes.
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http://dx.doi.org/10.1016/j.cophys.2019.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454996PMC
April 2020

The Long Noncoding RNA Paupar Modulates PAX6 Regulatory Activities to Promote Alpha Cell Development and Function.

Cell Metab 2019 12 10;30(6):1091-1106.e8. Epub 2019 Oct 10.

Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA; Barbara Davis Center, University of Colorado Medical Center, Aurora, CO 80045, USA. Electronic address:

Many studies have highlighted the role of dysregulated glucagon secretion in the etiology of hyperglycemia and diabetes. Accordingly, understanding the mechanisms underlying pancreatic islet α cell development and function has important implications for the discovery of new therapies for diabetes. In this study, comparative transcriptome analyses between embryonic mouse pancreas and adult mouse islets identified several pancreatic lncRNAs that lie in close proximity to essential pancreatic transcription factors, including the Pax6-associated lncRNA Paupar. We demonstrate that Paupar is enriched in glucagon-producing α cells where it promotes the alternative splicing of Pax6 to an isoform required for activation of essential α cell genes. Consistently, deletion of Paupar in mice resulted in dysregulation of PAX6 α cell target genes and corresponding α cell dysfunction, including blunted glucagon secretion. These findings illustrate a distinct mechanism by which a pancreatic lncRNA can coordinate glucose homeostasis by cell-specific regulation of a broadly expressed transcription factor.
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http://dx.doi.org/10.1016/j.cmet.2019.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205457PMC
December 2019

The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p.

Nat Commun 2015 Dec 21;6:10077. Epub 2015 Dec 21.

Program in Molecular Biology, University of Colorado, Denver, Anschutz Medical Campus, 12800 East 19th Avenue, Aurora, Colorado 80045, USA.

TP53 is mutated in 50% of all cancers, and its function is often compromised in cancers where it is not mutated. Here we demonstrate that the pro-tumorigenic/metastatic Six1 homeoprotein decreases p53 levels through a mechanism that does not involve the negative regulator of p53, MDM2. Instead, Six1 regulates p53 via a dual mechanism involving upregulation of microRNA-27a and downregulation of ribosomal protein L26 (RPL26). Mutation analysis confirms that RPL26 inhibits miR-27a binding and prevents microRNA-mediated downregulation of p53. The clinical relevance of this interaction is underscored by the finding that Six1 expression strongly correlates with decreased RPL26 across numerous tumour types. Importantly, we find that Six1 expression leads to marked resistance to therapies targeting the p53-MDM2 interaction. Thus, we identify a competitive mechanism of p53 regulation, which may have consequences for drugs aimed at reinstating p53 function in tumours.
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http://dx.doi.org/10.1038/ncomms10077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703841PMC
December 2015

A physiological role for connective tissue growth factor in early wound healing.

Lab Invest 2013 Jan 19;93(1):81-95. Epub 2012 Nov 19.

Departments of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.

Mesenchymal stem cells (MSCs) that overexpress secreted frizzled-related protein 2 (sFRP2) exhibit an enhanced reparative phenotype. The secretomes of sFRP2-overexpressing MSCs and vector control-MSCs were compared through liquid chromatography tandem mass spectrometry. Proteomic profiling revealed that connective tissue growth factor (CTGF; CCN2) was overrepresented in the conditioned media of sFRP2-overexpressing MSCs and MSC-derived CTGF could thus be an important paracrine effector. Subcutaneously implanted, MSC-loaded polyvinyl alcohol (PVA) sponges and stented excisional wounds were used as wound models to study the dynamics of CTGF expression. Granulation tissue generated within the sponges and full-thickness skin wounds showed transient upregulation of CTGF expression by MSCs and fibroblasts, implying a role for this molecule in early tissue repair. Although collagen and COL1A2 mRNA were not increased when recombinant CTGF was administered to sponges during the early phase (day 1-6) of tissue repair, prolonged administration (>15 days) of exogenous CTGF into PVA sponges resulted in fibroblast proliferation and increased deposition of collagen within the experimental granulation tissue. In support of its physiological role, CTGF immunoinhibition during early repair (days 0-7) reduced the quantity, organizational quality and vascularity of experimental granulation tissue in the sponge model. However, CTGF haploinsufficiency was not enough to reduce collagen deposition in excisional wounds. Similar to acute murine wound models, CTGF was transiently present in the early phase of human acute burn wound healing. Together, these results further support a physiological role for CTGF in wound repair and demonstrate that when CTGF expression is confined to early tissue repair, it serves a pro-reparative role. These data also further illustrate the potential of MSC-derived paracrine modulators to enhance tissue repair.
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http://dx.doi.org/10.1038/labinvest.2012.162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3720136PMC
January 2013

Connective tissue growth factor acts within both endothelial cells and beta cells to promote proliferation of developing beta cells.

Proc Natl Acad Sci U S A 2011 Sep 29;108(37):15242-7. Epub 2011 Aug 29.

Department of Molecular Physiology and Biophysics, Division of Diabetes, Vanderbilt University Medical Center, Nashville, TN 37232, USA.

Type 1 and type 2 diabetes result from an absolute or relative reduction in functional β-cell mass. One approach to replacing lost β-cell mass is transplantation of cadaveric islets; however, this approach is limited by lack of adequate donor tissue. Therefore, there is much interest in identifying factors that enhance β-cell differentiation and proliferation in vivo or in vitro. Connective tissue growth factor (CTGF) is a secreted molecule expressed in endothelial cells, pancreatic ducts, and embryonic β cells that we previously showed is required for β-cell proliferation, differentiation, and islet morphogenesis during development. The current study investigated the tissue interactions by which CTGF promotes normal pancreatic islet development. We found that loss of CTGF from either endothelial cells or β cells results in decreased embryonic β-cell proliferation, making CTGF unique as an identified β cell-derived factor that regulates embryonic β-cell proliferation. Endothelial CTGF inactivation was associated with decreased islet vascularity, highlighting the proposed role of endothelial cells in β-cell proliferation. Furthermore, CTGF overexpression in β cells during embryogenesis using an inducible transgenic system increased islet mass at birth by promoting proliferation of immature β cells, in the absence of changes in islet vascularity. Together, these findings demonstrate that CTGF acts in an autocrine manner during pancreas development and suggest that CTGF has the potential to enhance expansion of immature β cells in directed differentiation or regeneration protocols.
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http://dx.doi.org/10.1073/pnas.1100072108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3174622PMC
September 2011

OASIS/CREB3L1 induces expression of genes involved in extracellular matrix production but not classical endoplasmic reticulum stress response genes in pancreatic beta-cells.

Endocrinology 2010 Sep 28;151(9):4146-57. Epub 2010 Jul 28.

Division of Cellular and Molecular Biology, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada M5G1L7.

Old astrocyte specifically induced substance (OASIS) has previously been shown to be a putative endoplasmic reticulum (ER) stress sensor in astrocytes with a mechanism of activation that is similar to ATF6. In this study we investigated the expression and activation of endogenous and overexpressed OASIS in pancreatic beta-cells. OASIS mRNA expression was detected in pancreatic beta-cell lines and rodent islets, and the expression level was up-regulated by ER stress-inducing compounds. Endogenous OASIS protein, however, is expressed at low levels in pancreatic beta-cell lines and rodent islets, possibly due to abundant levels of the micro-RNA miR-140 present in these cells. In contrast, expression of both full-length and cleaved (active) OASIS was readily detectable in the developing mouse pancreas (embryonic d 15.5). Microarray analysis after expression of an active nuclear-localized version of OASIS in an inducible INS-1 beta-cell line resulted in the up-regulation of many genes implicated in extracellular matrix production and protein transport but not classical ER stress response genes. Consistent with this, expression of active OASIS failed to induce glucose-regulated protein 78 kDa promoter activity in pancreatic beta-cells. These results suggest that the repertoire of genes induced by OASIS is cell type-dependent and that the OASIS protein may have a role in pancreas development.
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http://dx.doi.org/10.1210/en.2010-0137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940493PMC
September 2010

Pancreas cell fate.

Birth Defects Res C Embryo Today 2009 Sep;87(3):232-48

Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Diabetes is characterized by decreased function of insulin-producing beta cells and insufficient insulin output resulting from an absolute (Type 1) or relative (Type 2) inadequate functional beta cell mass. Both forms of the disease would greatly benefit from treatment strategies that could enhance beta cell regeneration and/or function. Successful and reliable methods of generating beta cells or whole islets from progenitor cells in vivo or in vitro could lead to restoration of beta cell mass in individuals with Type 1 diabetes and enhanced beta cell compensation in Type 2 patients. A thorough understanding of the normal developmental processes that occur during pancreatic organogenesis, for example, transcription factors, cell signaling molecules, and cell-cell interactions that regulate endocrine differentiation from the embryonic pancreatic epithelium, is required in order to successfully reach these goals. This review summarizes our current understanding of pancreas development, with particular emphasis on factors intrinsic or extrinsic to the pancreatic epithelium that are involved in regulating the development and differentiation of the various pancreatic cell types. We also discuss the recent progress in generating insulin-producing cells from progenitor sources.
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http://dx.doi.org/10.1002/bdrc.20156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755625PMC
September 2009

Connective tissue growth factor (CTGF) inactivation leads to defects in islet cell lineage allocation and beta-cell proliferation during embryogenesis.

Mol Endocrinol 2009 Mar 8;23(3):324-36. Epub 2009 Jan 8.

Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, 2213 Garland Avenue, 7425C MRBIV, Nashville, Tennessee 37232-0475, USA.

The factors necessary for normal pancreatic islet morphogenesis have not been well characterized. Here we report that connective tissue growth factor (CTGF) is involved in the establishment of normal islet endocrine cell ratio and architecture. CTGF is a secreted protein known to modulate several growth factor-signaling pathways including TGF-beta, BMP, and Wnt. Although its role in pancreatic diseases such as pancreatitis and pancreatic cancer are well documented, a role for CTGF in normal pancreas development and function has heretofore not been examined. Using a lacZ-tagged CTGF allele, we describe for the first time the expression pattern of CTGF in the developing pancreas and the requirement of CTGF for normal islet morphogenesis and embryonic beta-cell proliferation. CTGF is highly expressed in pancreatic ductal epithelium and vascular endothelium, as well as at lower levels in developing insulin(+) cells, but becomes down-regulated in beta-cells soon after birth. Pancreata from CTGF null embryos have an increase in glucagon(+) cells with a concomitant decrease in insulin(+) cells, and show defects in islet morphogenesis. Loss of CTGF also results in a dramatic decrease in beta-cell proliferation at late gestation. Unlike CTGF null embryos, CTGF heterozygotes survive past birth and exhibit a range of islet phenotypes, including an intermingling of islet cell types, increased number of glucagon(+) cells, and beta-cell hypertrophy.
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http://dx.doi.org/10.1210/me.2008-0045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2654514PMC
March 2009