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5. Diabetes relief in mice by glucose-sensing insulin-secreting human [alpha]-cells

Author

Furuyama, Kenichiro, Chera, Simona, van Gurp, Léon, Oropeza, Daniel, Ghila, Luiza, Damond, Nicolas, and Vethe, Heidrun

Subjects
Pancreatic beta cells -- Research, Diabetes research, Diabetes mellitus -- Care and treatment, DNA binding proteins, Glucagon, Insulin, Displays (Marketing), Glucose, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Cell-identity switches, in which terminally differentiated cells are converted into different cell types when stressed, represent a widespread regenerative strategy in animals, yet they are poorly documented in mammals. In mice, some glucagon-producing pancreatic [alpha]-cells and somatostatin-producing [delta]-cells become insulin-expressing cells after the ablation of insulin-secreting [beta]-cells, thus promoting diabetes recovery. Whether human islets also display this plasticity, especially in diabetic conditions, remains unknown. Here we show that islet non-[beta]-cells, namely [alpha]-cells and pancreatic polypeptide (PPY)-producing [gamma]-cells, obtained from deceased non-diabetic or diabetic human donors, can be lineage-traced and reprogrammed by the transcription factors PDX1 and MAFA to produce and secrete insulin in response to glucose. When transplanted into diabetic mice, converted human [alpha]-cells reverse diabetes and continue to produce insulin even after six months. Notably, insulin-producing [alpha]-cells maintain expression of [alpha]-cell markers, as seen by deep transcriptomic and proteomic characterization. These observations provide conceptual evidence and a molecular framework for a mechanistic understanding of in situ cell plasticity as a treatment for diabetes and other degenerative diseases. Islet non-[beta]-cells from non-diabetic and diabetic human donors are modified via the transcription factors PDX1 and MAFA to produce and secrete insulin in response to glucose., Author(s): Kenichiro Furuyama [sup.1] , Simona Chera [sup.1] [sup.2] , Léon van Gurp [sup.1] , Daniel Oropeza [sup.1] , Luiza Ghila [sup.1] [sup.2] , Nicolas Damond [sup.1] , Heidrun Vethe [...]

Published
2019
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6. Increased β-cell proliferation before immune cell invasion prevents progression of type 1 diabetes

Author

Dirice, Ercument, Kahraman, Sevim, De Jesus, Dario F., El Ouaamari, Abdelfattah, Basile, Giorgio, Baker, Rocky L., Yigit, Burcu, Piehowski, Paul D., Kim, Mi-Jeong, Dwyer, Alexander J., Ng, Raymond W. S., Schuster, Cornelia, Vethe, Heidrun, Martinov, Tijana, Ishikawa, Yuki, Teo, Adrian Kee Keong, Smith, Richard D., Hu, Jiang, Haskins, Kathryn, Serwold, Thomas, Qian, Wei-Jun, Fife, Brian T., Kissler, Stephan, and Kulkarni, Rohit N.

Published
2019
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7. Global and single-cell proteomics view of the co-evolution between neural progenitors and breast cancer cells in a co-culture model

Author

Bjoernstad, Ole Vidhammer, primary, Fernandez, Manuel Carrasco, additional, Finne, Kenneth, additional, Winge, Ingeborg, additional, Askeland, Cecilie, additional, Arnes, Jarle Birger, additional, Knutsvik, Goril, additional, Kleftogiannis, Dimitrios, additional, Paulo, Joao A., additional, Akslen, Lars Andreas, additional, and Vethe, Heidrun, additional

Published
2023
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11. Neurogenesis and angiogenesis are associated features of aggressive breast cancer

Author

Wik, Elisabeth, primary, Aziz, Sura, additional, Vethe, Heidrun, additional, Askeland, Cecilie, additional, Finne, Kenneth, additional, Knutsvik, Goril, additional, Winge, Ingeborg, additional, Kruger, Kristi, additional, Mannelqvist, Monica, additional, Svanoe, Amalie Abrahamsen, additional, Birkeland, Even, additional, Kjolle, Silje, additional, Davidsen, Benedicte, additional, Aas, Turid, additional, Stefansson, Ingunn Marie, additional, Kleftogiannis, Dimitrios, additional, and Akslen, Lars Andreas, additional

Published
2022
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14. Linagliptin Ameliorates Hepatic Steatosis via Non-Canonical Mechanisms in Mice Treated with a Dual Inhibitor of Insulin Receptor and IGF-1 Receptor

Author

Okuyama, Tomoko, primary, Shirakawa, Jun, additional, Tajima, Kazuki, additional, Ino, Yoko, additional, Vethe, Heidrun, additional, Togashi, Yu, additional, Kyohara, Mayu, additional, Inoue, Ryota, additional, Miyashita, Daisuke, additional, Li, Jinghe, additional, Goto, Nozomi, additional, Ichikawa, Taiga, additional, Yamasaki, Shingo, additional, Ohnuma, Haruka, additional, Takayanagi, Rie, additional, Kimura, Yayoi, additional, Hirano, Hisashi, additional, and Terauchi, Yasuo, additional

Published
2020
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17. Modulating Wnt signaling in human induced pluripotent stem cell-derived S7 cells

Author

Vethe, Heidrun, Ghila, Luiza, Berle, Magnus, Hoareau, Laurence, Haaland, Øystein Ariansen, Scholz, Hanne, Paulo, Joao A., Chera, Simona, and Ræder, Helge

Abstract

Current published protocols for targeted differentiation of human stem cells toward pancreatic β-cells fail to deliver sufficiently mature cells with functional properties comparable to human islet β-cells. We aimed to assess whether Wnt-modulation could promote the final protocol stages of β-cell maturation, building our hypothesis on our previous findings of Wnt activation in immature hiPSC-derived stage 7 (S7) cells compared to adult human islets and with recent data reporting a link between Wnt/PCP and in vitro β-cell maturation. In this study, we stimulated canonical and non-canonical Wnt signaling in hiPSC-derived S7 cells using syntetic proteins including WNT3A, WNT4, WNT5A and WNT5B, and we inhibited endogenous Wnt signaling with the Tankyrase inhibitor G007-LK (TKi). Whereas neither canonical nor non-canonical Wnt stimulation alone was able to mature hiPSC-derived S7 cells, WNT-inhibition with TKi increased the fraction of monohormonal cells and global proteomics of TKi-treated S7 cells showed a proteomic signature more similar to adult human islets, suggesting that inhibition of endogenous Wnt contributes toward final β-cell maturation. publishedVersion

Published
2019

18. Dynamic proteome profiling of human pluripotent stem cell-derived pancreatic progenitors

Author

Loo, Larry Sai Weng, primary, Vethe, Heidrun, additional, Soetedjo, Andreas Alvin Purnomo, additional, Paulo, Joao A., additional, Jasmen, Joanita, additional, Jackson, Nicholas, additional, Bjørlykke, Yngvild, additional, Valdez, Ivan A., additional, Vaudel, Marc, additional, Barsnes, Harald, additional, Gygi, Steven P., additional, Ræder, Helge, additional, Teo, Adrian Kee Keong, additional, and Kulkarni, Rohit N., additional

Published
2020
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22. Diabetes relief in mice by glucose-sensing insulin-secreting human α-cells

Author

Furuyama, Kenichiro, primary, Chera, Simona, additional, van, Gurp Leon, additional, Oropeza, Daniel, additional, Ghila, Luiza, additional, Damond, Nicolas, additional, Vethe, Heidrun, additional, Paulo, Joao A, additional, Joosten, Antoinette M, additional, Berney, Thierry, additional, Bosco, Domenico, additional, Dorrell, Craig, additional, Grompe, Markus, additional, Raeder, Helge, additional, Roep, Bart O, additional, Thorel, Fabrizio, additional, and Herrera, Pedro L, additional

Published
2019
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26. Diabetes relief in mice by glucose-sensing insulin-secreting human α-cells.

Author

Furuyama, Kenichiro, Chera, Simona, van Gurp, Léon, Oropeza, Daniel, Ghila, Luiza, Damond, Nicolas, Vethe, Heidrun, Paulo, Joao A., Joosten, Antoinette M., Berney, Thierry, Bosco, Domenico, Dorrell, Craig, Grompe, Markus, Ræder, Helge, Roep, Bart O., Thorel, Fabrizio, and Herrera, Pedro L.

Abstract

Cell-identity switches, in which terminally differentiated cells are converted into different cell types when stressed, represent a widespread regenerative strategy in animals, yet they are poorly documented in mammals. In mice, some glucagon-producing pancreatic α-cells and somatostatin-producing δ-cells become insulin-expressing cells after the ablation of insulin-secreting β-cells, thus promoting diabetes recovery. Whether human islets also display this plasticity, especially in diabetic conditions, remains unknown. Here we show that islet non-β-cells, namely α-cells and pancreatic polypeptide (PPY)-producing γ-cells, obtained from deceased non-diabetic or diabetic human donors, can be lineage-traced and reprogrammed by the transcription factors PDX1 and MAFA to produce and secrete insulin in response to glucose. When transplanted into diabetic mice, converted human α-cells reverse diabetes and continue to produce insulin even after six months. Notably, insulin-producing α-cells maintain expression of α-cell markers, as seen by deep transcriptomic and proteomic characterization. These observations provide conceptual evidence and a molecular framework for a mechanistic understanding of in situ cell plasticity as a treatment for diabetes and other degenerative diseases. Islet non-β-cells from non-diabetic and diabetic human donors are modified via the transcription factors PDX1 and MAFA to produce and secrete insulin in response to glucose. [ABSTRACT FROM AUTHOR]

Published
2019
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27. Mass spectrometry-based proteomics of human cerebrospinal fluid. Biomarker discovery and verification in multiple sclerosis

Author

Vethe, Heidrun

Subjects
Multiple sclerosis, Medical disciplines: 700::Clinical medical disciplines: 750::Neurology: 752 [VDP], cerebrospinal fluid
Abstract

The main focus of this study was to use mass spectrometry-based proteomics to study protein abundance in cerebrospinal fluid (CSF) to reveal proteins that could serve as biomarker candidates in multiple sclerosis (MScl). By combining a CSF pooling strategy and label-free relative quantification we discovered 65 proteins of differential abundance between MScl patients and controls. A selection of 17 biomarker candidates was further subjected to two independent verification steps: using stable isotope dimethyl labeling coupled to Accurate Inclusion Mass Screening (dimethyl-AIMS) and Stable Isotope Dilution Selected Reaction Monitoring (SID-SRM) for targeted quantification. The SID-SRM study included a larger patient cohort of 125 cases and controls. To our knowledge, this is the first report of a larger SRM verification study for biomarker candidates in MScl. The most interesting results from the biomarker discovery and verification study were the significantly decreased abundance of Apolipoprotein D, Cystatin C, Kallikrein-6 and Alpha-1-acid glycoprotein 1 in MScl patients compared to controls. Furthermore, we performed a comprehensive characterization of the normal CSF proteome. We identified 18, 807 peptide mapping to 1987 proteins by applying immuno-affinity depletion and SDS-PAGE for enhanced proteome coverage. We obtain a comprehensive set of reference proteins that could further be used for investigations in MScl. The experiment gave us the opportunity to examine the size distribution on the SDS-PAGE gel of a selection of biomarker candidate proteins in normal CSF, with the aim to reveal potential protein variants (isoforms, truncation products and proteolytic processed products). We hypothesized that the identification of non-tryptic peptides could indicate truncation products of proteins in CSF. 13 and nine non-tryptic peptides were identified for the biomarker candidates Cystatin C and Secretogranin-1, respectively. This information had immediate utility for investigation in MScl. Based on the observed spread in size distribution of biomarker candidate proteins in normal CSF, we aimed to obtain quantitative information of proteins present in both high and low mass fractions on the gel and further target these proteins to obtain an abundance ratio between RRMS (patients) and OIND (controls), and investigate if these ratios differed for the same protein. The most striking observation was the opposite regulation level in CSF of Secretogranin-1. Master i Medisinsk biologi MAMD-MEDBI BMED395

Published
2012

29. Distinct protein signature of hypertension-induced damage in the renal proteome of the two-kidney, one-clip rat model

Author

Vethe, Heidrun, Finne, Kenneth, Skogstrand, Trude, Vaudel, Marc, Vikse, Bjørn E, Hultström, Michael, Placier, Sandrine, Scherer, Andreas, Tenstad, Olav, Marti, Hans-Peter, Vethe, Heidrun, Finne, Kenneth, Skogstrand, Trude, Vaudel, Marc, Vikse, Bjørn E, Hultström, Michael, Placier, Sandrine, Scherer, Andreas, Tenstad, Olav, and Marti, Hans-Peter

Abstract

BACKGROUND: Hypertensive nephrosclerosis is one of the most frequent causes of chronic kidney failure. Proteome analysis potentially improves the pathophysiological understanding and diagnostic precision of this disorder. In the present exploratory study, we investigated experimental nephrosclerosis in the two-kidney, one-clip (2K1C) hypertensive rat model. METHODS: The renal cortex proteome from juxtamedullary cortex and outer cortex of 2K1C male Wistar-Hannover rats (n = 4) was compared with the sham-operated controls (n = 6), using mass spectrometry-based quantitative proteomics. We combined a high abundant plasma protein depletion strategy with an extended liquid chromatographic gradient to improve peptide and protein identification. Immunohistology was used for independent confirmation of abundance. RESULTS: We identified 1724 proteins, of which 1434 were quantified with at least two unique peptides. Comparative proteomics revealed 608 proteins, including the platelet-derived growth factor receptor-β signalling pathway, with different abundances between the non-clipped kidney of hypertensive 2K1C rats and the corresponding kidney of the normotensive controls (P < 0.05, absolute fold change ≥1.5). Among the most significantly altered proteins in the whole cortex were periostin, transgelin, and creatine kinase B-type. Relative abundance of periostin alone allowed clear classification of 2K1C and controls. Enrichment of periostin in 2K1C rats was verified by immunohistology, showing positivity especially around the fibrotic vessels. CONCLUSION: The proteome is altered in hypertension-induced kidney damage. We propose periostin, especially in combination with transgelin and creatine kinase B-type, as possible proteomic classifier to distinguish hypertensive nephrosclerosis from the normal tissue. This classifier needs to be further validated with respect to early diagnosis of fibrosis, prognosis, and its potential as a novel molecular target for pharmacological

Published
2015
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30. Quantitative proteomics suggests decrease in the secretogranin-1 cerebrospinal fluid levels during the disease course of multiple sclerosis.

Author

UCL - (SLuc) Service de neurologie, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, Kroksveen, Ann, Jaffe, Jacob D, Aasebo, Elise, Barsnes, Harald, Bjorlykke, Yngvild, Franciotta, Diego, Keshishian, Hasmik, Myhr, Kjell-Morten, Opsahl, Jill A., Van Pesch, Vincent, Teunissen, Charlotte E., Torkildsen, Oivind, Ulvik, Rune J., Vethe, Heidrun, Carr, Steven A., Berven, Frode S., UCL - (SLuc) Service de neurologie, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, Kroksveen, Ann, Jaffe, Jacob D, Aasebo, Elise, Barsnes, Harald, Bjorlykke, Yngvild, Franciotta, Diego, Keshishian, Hasmik, Myhr, Kjell-Morten, Opsahl, Jill A., Van Pesch, Vincent, Teunissen, Charlotte E., Torkildsen, Oivind, Ulvik, Rune J., Vethe, Heidrun, Carr, Steven A., and Berven, Frode S.

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS with unknown cause. Proteins with different abundance in the cerebrospinal fluid (CSF) from relapsing-remitting MS (RRMS) patients and neurological controls could give novel insight to the MS pathogenesis and be used to improve diagnosis, predict prognosis and disease course, and guide in therapy decisions. We combined iTRAQ labeling and Orbitrap mass spectrometry to discover proteins with different CSF abundance between six RRMS patients and 18 neurological disease controls. From 777 quantified proteins seven were selected as biomarker candidates, namely chitinase-3-like protein 1, secretogranin-1 (Sg1), cerebellin-1, neuroserpin, cell surface glycoprotein MUC18, testican-2 and glutamate receptor 4. An independent sample set of 13 early-MS patients, 13 RRMS patients and 13 neurological controls was used in a multiple reaction monitoring verification study. We found the intracellular calcium binding protein Sg1 to be increased in early-MS patients compared to RRMS and neurological controls. Sg1 should be included in further studies to elucidate its role in the early phases of MS pathogenesis and its potential as a biomarker for this disease. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Published
2015

31. Quantitative proteomics suggests decrease in the secretogranin‐1 cerebrospinal fluid levels during the disease course of multiple sclerosis

Author

Kroksveen, Ann C., primary, Jaffe, Jacob D., additional, Aasebø, Elise, additional, Barsnes, Harald, additional, Bjørlykke, Yngvild, additional, Franciotta, Diego, additional, Keshishian, Hasmik, additional, Myhr, Kjell‐Morten, additional, Opsahl, Jill A., additional, van Pesch, Vincent, additional, Teunissen, Charlotte E., additional, Torkildsen, Øivind, additional, Ulvik, Rune J., additional, Vethe, Heidrun, additional, Carr, Steven A., additional, and Berven, Frode S., additional

Published
2015
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34. DIFFERENTIAL PROTEOMICS OF EXPERIMENTAL HYPERTENSIVE RENAL DISEASE REVEALS DISTINCT PROTEIN SIGNATURES AND PERIOSTIN AS A DAMAGE MARKER

Author

Vethe, Heidrun, Finne, Kenneth, Skogstrand, Trude, Vaudel, Marc, Vikse, Bjorn Egil, Hultström, Michael, Placier, Sandrine, Scherer, Andreas, Tenstad, Olav, Marti, Hans-Peter P., Vethe, Heidrun, Finne, Kenneth, Skogstrand, Trude, Vaudel, Marc, Vikse, Bjorn Egil, Hultström, Michael, Placier, Sandrine, Scherer, Andreas, Tenstad, Olav, and Marti, Hans-Peter P.

Published
2014

37. Discovery and initial verification of differentially abundant proteins between multiple sclerosis patients and controls using iTRAQ and SID-SRM.

Author

UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, UCL - (SLuc) Service de neurologie, Kroksveen, Ann C, Aasebø, Elise, Vethe, Heidrun, Van Pesch, Vincent, Franciotta, Diego, Teunissen, Charlotte E, Ulvik, Rune J, Vedeler, Christian, Myhr, Kjell-Morten, Barsnes, Harald, Berven, Frode S, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, UCL - (SLuc) Service de neurologie, Kroksveen, Ann C, Aasebø, Elise, Vethe, Heidrun, Van Pesch, Vincent, Franciotta, Diego, Teunissen, Charlotte E, Ulvik, Rune J, Vedeler, Christian, Myhr, Kjell-Morten, Barsnes, Harald, and Berven, Frode S

Abstract

In the present study, we aimed to discover cerebrospinal fluid (CSF) proteins with significant abundance difference between early multiple sclerosis patients and controls, and do an initial verification of these proteins using selected reaction monitoring (SRM). iTRAQ and Orbitrap MS were used to compare the CSF proteome of patients with clinically isolated syndrome (CIS) (n=5), patients with relapsing-remitting multiple sclerosis that had CIS at the time of lumbar puncture (n=5), and controls with other inflammatory neurological disease (n=5). Of more than 1200 identified proteins, five proteins were identified with significant abundance difference between the patients and controls. In the initial verification using SRM we analyzed a larger patient and control cohort (n=132) and also included proteins reported as differentially abundant in multiple sclerosis in the literature. We found significant abundance difference for 11 proteins after verification, of which the five proteins alpha-1-antichymotrypsin, contactin-1, apolipoprotein D, clusterin, and kallikrein-6 were significantly differentially abundant in several of the group comparisons. This initial study form the basis for further biomarker verification studies in even larger sample cohorts, to determine if these proteins have relevance as diagnostic or prognostic biomarkers for multiple sclerosis.

Published
2013

39. Carboxyl-Ester Lipase Maturity-Onset Diabetes of the Young Disease Protein Biomarkers in Secretin-Stimulated Duodenal Juice

Author

Bjorlykke, Yngvild, Vethe, Heidrun, Vaudel, Marc, Barsnes, Harald, Berven, Frode S., Tjora, Erling, and Raeder, Helge

Abstract

Patients with carboxyl-ester lipase-maturity-onset diabetes of the young (CEL-MODY) display distinct disease stages toward the development of monogenic diabetes and exocrine pancreatic disease. The finding of differentially increased proteins, some related to MAPK signaling, in a discovery proteomics study of secretin-stimulated duodenal juice in three CEL-MODY patients, prompted us to monitor their abundance in an extensive number of CEL-MODY subjects at different disease stages and controls using targeted proteomics. In the current study, we demonstrate the feasibility of selected reaction monitoring assays to quantify protein levels in secretin-stimulated duodenal juice. Furthermore, we define a set of five peptides for potential use as diagnostic tests in CEL-MODY patients. Finally, we propose a further set of seven proteins with a likely pathogenic role in CEL-MODY disease progression.

Published
2015
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40. Global and single-cell proteomics view of the co-evolution between neural progenitors and breast cancer cells in a co-culture model.

Author

Bjørnstad OV, Carrasco M, Finne K, Winge I, Askeland C, Arnes JB, Knutsvik G, Kleftogiannis D, Paulo JA, Akslen LA, and Vethe H

Abstract

Tumor neurogenesis, a process by which new nerves invade tumors, is a growing area of interest in cancer research. Nerve presence has been linked to aggressive features of various solid tumors, including breast and prostate cancer. A recent study suggested that the tumor microenvironment may influence cancer progression through recruitment of neural progenitor cells from the central nervous system. However, the presence of neural progenitors in human breast tumors has not been reported. Here, we investigate the presence of Doublecortin (DCX) and Neurofilament-Light (NFL) co-expressing (DCX+/NFL+) cells in patient breast cancer tissue using Imaging Mass Cytometry. To map the interaction between breast cancer cells and neural progenitor cells further, we created an in vitro model mimicking breast cancer innervation, and characterized using mass spectrometry-based proteomics on the two cell types as they co- evolved in co-culture. Our results indicate stromal presence of DCX+/NFL+ cells in breast tumor tissue from a cohort of 107 patient cases, and that neural interaction contribute to drive a more aggressive breast cancer phenotype in our co-culture models. Our results support that neural involvement plays an active role in breast cancer and warrants further studies on the interaction between nervous system and breast cancer progression.

Published
2023
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41. Mapping Proteome Changes in Microsatellite Stable, Recurrent Colon Cancer Reveals a Significant Immune System Signature.

Author

Berle M, Hestetun KE, Vethe H, Chera S, Paulo JA, Dahl O, and Myklebust MP

Subjects
Humans, Microsatellite Repeats, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local immunology, Prognosis, Colonic Neoplasms genetics, Colonic Neoplasms immunology, Colonic Neoplasms pathology, Immune System, Proteome
Abstract

Background/aim: Better stratification of the risk of relapse will help select the right patients for adjuvant treatment and improve targeted therapies for patients with colon cancer., Materials and Methods: To understand why a subset of tumors relapse, we compared the proteome of two groups of patients with colon cancer with similar stage, stratified based on the presence or absence of recurrence., Results: Using tumor biopsies from the primary operation, we identified dissimilarity between recurrent and nonrecurrent mismatch satellite stable colon cancer and found that signaling related to immune activation and inflammation was associated with relapse., Conclusion: Immune modulation may have an effect on mismatch satellite stable colon cancer. At present, immune therapy is offered primarily to microsatellite instable colon cancer. Hopefully, immune therapy in mismatch satellite stable colon cancer beyond PD-1 and PD-L1 inhibitors can be implemented., (Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Published
2022
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