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3. Primate-specific ZNF808 is essential for pancreatic development in humans

Author

De Franco, Elisa, Owens, Nick D. L., Montaser, Hossam, Wakeling, Matthew N., Saarimäki-Vire, Jonna, Triantou, Athina, Ibrahim, Hazem, Balboa, Diego, Caswell, Richard C., Jennings, Rachel E., Kvist, Jouni A., Johnson, Matthew B., Muralidharan, Sachin, Ellard, Sian, Wright, Caroline F., Maddirevula, Sateesh, Alkuraya, Fowzan S., Hanley, Neil A., Flanagan, Sarah E., Otonkoski, Timo, Hattersley, Andrew T., and Imbeault, Michael

Published
2023
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7. The N-glycome of human embryonic stem cells

Author

Olonen Anne, Aitio Olli, Jaatinen Taina, Tiittanen Minna, Blomqvist Maria, Olsson Cia, Mikkola Milla, Heiskanen Annamari, Satomaa Tero, Helin Jari, Hiltunen Jukka, Natunen Jari, Tuuri Timo, Otonkoski Timo, Saarinen Juhani, and Laine Jarmo

Subjects
Cytology, QH573-671
Abstract

Abstract Background Complex carbohydrate structures, glycans, are essential components of glycoproteins, glycolipids, and proteoglycans. While individual glycan structures including the SSEA and Tra antigens are already used to define undifferentiated human embryonic stem cells (hESC), the whole spectrum of stem cell glycans has remained unknown. We undertook a global study of the asparagine-linked glycoprotein glycans (N-glycans) of hESC and their differentiated progeny using MALDI-TOF mass spectrometric and NMR spectroscopic profiling. Structural analyses were performed by specific glycosidase enzymes and mass spectrometric fragmentation analyses. Results The data demonstrated that hESC have a characteristic N-glycome which consists of both a constant part and a variable part that changes during hESC differentiation. hESC-associated N-glycans were downregulated and new structures emerged in the differentiated cells. Previously mouse embryonic stem cells have been associated with complex fucosylation by use of SSEA-1 antibody. In the present study we found that complex fucosylation was the most characteristic glycosylation feature also in undifferentiated hESC. The most abundant complex fucosylated structures were Lex and H type 2 antennae in sialylated complex-type N-glycans. Conclusion The N-glycan phenotype of hESC was shown to reflect their differentiation stage. During differentiation, hESC-associated N-glycan features were replaced by differentiated cell-associated structures. The results indicated that hESC differentiation stage can be determined by direct analysis of the N-glycan profile. These results provide the first overview of the N-glycan profile of hESC and form the basis for future strategies to target stem cell glycans.

Published
2009
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8. Gene expression signature predicts rate of type 1 diabetes progression

Author

Mathieu, Chantal, Gillard, Pieter, Casteels, Kristina, Overbergh, Lutgart, Dunger, David, Wallace, Chris, Evans, Mark, Thankamony, Ajay, Hendriks, Emile, Bruggraber, Sylvaine, Marcoveccchio, Loredana, Peakman, Mark, Tree, Timothy, Morgan, Noel G., Richardson, Sarah, Todd, John A., Wicker, Linda, Mander, Adrian, Dayan, Colin, Alhadj Ali, Mohammad, Pieber, Thomas, Eizirik, Decio L., Cnop, Myriam, Brunak, Søren, Pociot, Flemming, Johannesen, Jesper, Rossing, Peter, Quigley, Cristina Legido, Mallone, Roberto, Scharfmann, Raphael, Boitard, Christian, Knip, Mikael, Otonkoski, Timo, Veijola, Riitta, Lahesmaa, Riitta, Oresic, Matej, Toppari, Jorma, Danne, Thomas, Ziegler, Anette G., Achenbach, Peter, Rodriguez-Calvo, Teresa, Solimena, Michele, Bonifacio, Ezio E., Speier, Stephan, Holl, Reinhard, Dotta, Francesco, Chiarelli, Francesco, Marchetti, Piero, Bosi, Emanuele, Cianfarani, Stefano, Ciampalini, Paolo, De Beaufort, Carine, Dahl-Jørgensen, Knut, Skrivarhaug, Torild, Joner, Geir, Krogvold, Lars, Jarosz-Chobot, Przemka, Battelino, Tadej, Thorens, Bernard, Gotthardt, Martin, Roep, Bart O., Nikolic, Tanja, Zaldumbide, Arnaud, Lernmark, Ake, Lundgren, Marcus, Costacalde, Guillaume, Strube, Thorsten, Schulte, Anke M., Nitsche, Almut, Vela, Jose, Von Herrath, Matthias, Wesley, Johnna, Napolitano-Rosen, Antonella, Thomas, Melissa, Schloot, Nanette, Goldfine, Allison, Waldron-Lynch, Frank, Kompa, Jill, Vedala, Aruna, Hartmann, Nicole, Nicolas, Gwenaelle, van Rampelbergh, Jean, Bovy, Nicolas, Dutta, Sanjoy, Soderberg, Jeannette, Ahmed, Simi, Martin, Frank, Latres, Esther, Agiostratidou, Gina, Koralova, Anne, Willemsen, Ruben, Smith, Anne, Anand, Binu, Datta, Vipan, Puthi, Vijith, Zac-Varghese, Sagen, Dias, Renuka, Sundaram, Premkumar, Vaidya, Bijay, Patterson, Catherine, Owen, Katharine, Piel, Barbara, Heller, Simon, Randell, Tabitha, Gazis, Tasso, Reismen, Elise Bismuth, Carel, Jean-Claude, Riveline, Jean-Pierre, Gautier, Jean-Francoise, Andreelli, Fabrizion, Travert, Florence, Cosson, Emmanuel, Penfornis, Alfred, Petit, Catherine, Feve, Bruno, Lucidarme, Nadine, Beressi, Jean-Paul, Ajzenman, Catherina, Radu, Alina, Greteau-Hamoumou, Stephanie, Bibal, Cecile, Meissner, Thomas, Heidtmann, Bettina, Toni, Sonia, Rami-Merhar, Birgit, Eeckhout, Bart, Peene, Bernard, Vantongerloo, N., Maes, Toon, Gommers, Leen, Suomi, Tomi, Starskaia, Inna, Kalim, Ubaid Ullah, Rasool, Omid, Jaakkola, Maria K., Grönroos, Toni, Välikangas, Tommi, Brorsson, Caroline, Mazzoni, Gianluca, Overbergh, Lut, Chmura, Piotr, and Elo, Laura L.

Published
2023
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9. Comprehensive characterization of the embryonic factor LEUTX

Author

Gawriyski, Lisa, Jouhilahti, Eeva-Mari, Yoshihara, Masahito, Fei, Liangru, Weltner, Jere, Airenne, Tomi T., Trokovic, Ras, Bhagat, Shruti, Tervaniemi, Mari H., Murakawa, Yasuhiro, Salokas, Kari, Liu, Xiaonan, Miettinen, Sini, Bürglin, Thomas R., Sahu, Biswajyoti, Otonkoski, Timo, Johnson, Mark S., Katayama, Shintaro, Varjosalo, Markku, and Kere, Juha

Published
2023
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10. Functional, metabolic and transcriptional maturation of human pancreatic islets derived from stem cells

Author

Balboa, Diego, Barsby, Tom, Lithovius, Väinö, Saarimäki-Vire, Jonna, Omar-Hmeadi, Muhmmad, Dyachok, Oleg, Montaser, Hossam, Lund, Per-Eric, Yang, Mingyu, Ibrahim, Hazem, Näätänen, Anna, Chandra, Vikash, Vihinen, Helena, Jokitalo, Eija, Kvist, Jouni, Ustinov, Jarkko, Nieminen, Anni I., Kuuluvainen, Emilia, Hietakangas, Ville, Katajisto, Pekka, Lau, Joey, Carlsson, Per-Ola, Barg, Sebastian, Tengholm, Anders, and Otonkoski, Timo

Published
2022
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19. Efficient Vascular and Neural Engraftment of Stem Cell–Derived Islets.

Author

Thorngren, Julia, Brboric, Anja, Vasylovska, Svitlana, Hjelmqvist, Daisy, Westermark, Gunilla T., Saarimäki-Vire, Jonna, Kvist, Jouni, Balboa, Diego, Otonkoski, Timo, Carlsson, Per-Ola, and Lau, Joey

Subjects
ISLANDS, VASCULAR endothelium, BLOOD vessels
Abstract

Pluripotent stem cell–derived islets (SC-islets) have emerged as a new source for β-cell replacement therapy. The function of human islet transplants is hampered by excessive cell death posttransplantation; contributing factors include inflammatory reactions, insufficient revascularization, and islet amyloid formation. However, there is a gap in knowledge of the engraftment process of SC-islets. In this experimental study, we investigated the engraftment capability of SC-islets at 3 months posttransplantation and observed that cell apoptosis rates were lower but vascular density was similar in SC-islets compared with human islets. Whereas the human islet transplant vascular structures were a mixture of remnant donor endothelium and ingrowing blood vessels, the SC-islets contained ingrowing blood vessels only. Oxygenation in the SC-islet grafts was twice as high as that in the corresponding grafts of human islets, suggesting better vascular functionality. Similar to the blood vessel ingrowth, reinnervation of the SC-islets was four- to fivefold higher than that of the human islets. Both SC-islets and human islets contained amyloid at 1 and 3 months posttransplantation. We conclude that the vascular and neural engraftment of SC-islets are superior to those of human islets, but grafts of both origins develop amyloid, with potential long-term consequences. Article Highlights: There is a gap in knowledge of the engraftment process of stem cell–derived islets (SC-islets). We investigated the engraftment capability of SC-islets compared with that of human islets after transplantation. Vascular density was similar in SC-islets and human islets, but neural density was four- to fivefold higher in SC-islets than in human islets. Vascular and neural engraftment of SC-islets are superior to those of human islets. [ABSTRACT FROM AUTHOR]

Published
2024
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22. YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress

Author

De Franco, Elisa, Lytrivi, Maria, Ibrahim, Hazem, Montaser, Hossam, Wakeling, Matthew N., Fantuzzi, Federica, Patel, Kashyap, Demarez, Celine, Cai, Ying, Igoillo-Esteve, Mariana, Cosentino, Cristina, Lithovius, Vaino, Vihinen, Helena, Jokitalo, Eija, Laver, Thomas W., Johnson, Matthew B., Sawatani, Toshiaki, Shakeri, Hadis, Pachera, Nathalie, Haliloglu, Belma, Ozbek, Mehmet Nuri, Unal, Edip, Yildirim, Ruken, Godbole, Tushar, Yildiz, Melek, Aydin, Banu, Bilheu, Angeline, Suzuki, Ikuo, Flanagan, Sarah E., Vanderhaeghen, Pierre, Senee, Valerie, Julier, Cecile, Marchetti, Piero, Eizirik, Decio L., Ellard, Sian, Saarimaki-Vire, Jonna, Otonkoski, Timo, Cnop, Miriam, and Hattersley, Andrew T.

Subjects
Pediatric research, Diabetes mellitus -- Genetic aspects -- Causes of -- Development and progression, Microcephaly -- Genetic aspects -- Causes of -- Development and progression, Stress (Physiology) -- Genetic aspects -- Health aspects, Neonatal diseases -- Genetic aspects -- Causes of -- Development and progression, Endoplasmic reticulum -- Physiological aspects -- Health aspects, Health care industry
Abstract

Neonatal diabetes is caused by single gene mutations reducing pancreatic [beta] cell number or impairing [beta] cell function. Understanding the genetic basis of rare diabetes subtypes highlights fundamental biological processes in [beta] cells. We identified 6 patients from 5 families with homozygous mutations in the YIPF5 gene, which is involved in trafficking between the endoplasmic reticulum (ER) and the Golgi. All patients had neonatal/early-onset diabetes, severe microcephaly, and epilepsy. YIPF5 is expressed during human brain development, in adult brain and pancreatic islets. We used 3 human [beta] cell models (YIPF5 silencing in EndoC-[beta]H1 cells, YIPF5 knockout and mutation knockin in embryonic stem cells, and patient-derived induced pluripotent stem cells) to investigate the mechanism through which YIPF5 loss of function affects [beta] cells. Loss of YIPF5 function in stem cell-derived islet cells resulted in proinsulin retention in the ER, marked ER stress, and p cell failure. Partial YIPF5 silencing in EndoC-[beta]H1 cells and a patient mutation in stem cells increased the [beta] cell sensitivity to ER stress-induced apoptosis. We report recessive YIPF5 mutations as the genetic cause of a congenital syndrome of microcephaly, epilepsy, and neonatal/early-onset diabetes, highlighting a critical role of YIPF5 in [beta] cells and neurons. We believe this is the first report of mutations disrupting the ER-to-Golgi trafficking, resulting in diabetes., Introduction Neonatal diabetes mellitus develops before 6 months of age and is caused by reduced pancreatic [beta] cell number (reduced formation/increased destruction) or impaired [beta] cell function. Previous studies have [...]

Published
2020
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23. Proinsulin folding and trafficking defects trigger a common pathological disturbance of endoplasmic reticulum homeostasis.

Author

Arunagiri, Anoop, Alam, Maroof, Haataja, Leena, Draz, Hassan, Alasad, Bashiyer, Samy, Praveen, Sadique, Nadeed, Tong, Yue, Cai, Ying, Shakeri, Hadis, Fantuzzi, Federica, Ibrahim, Hazem, Jang, Insook, Sidarala, Vaibhav, Soleimanpour, Scott A., Satin, Leslie S., Otonkoski, Timo, Cnop, Miriam, Itkin‐Ansari, Pamela, and Kaufman, Randal J.

Abstract

Primary defects in folding of mutant proinsulin can cause dominant‐negative proinsulin accumulation in the endoplasmic reticulum (ER), impaired anterograde proinsulin trafficking, perturbed ER homeostasis, diminished insulin production, and β‐cell dysfunction. Conversely, if primary impairment of ER‐to‐Golgi trafficking (which also perturbs ER homeostasis) drives misfolding of nonmutant proinsulin—this might suggest bi‐directional entry into a common pathological phenotype (proinsulin misfolding, perturbed ER homeostasis, and deficient ER export of proinsulin) that can culminate in diminished insulin storage and diabetes. Here, we've challenged β‐cells with conditions that impair ER‐to‐Golgi trafficking, and devised an accurate means to assess the relative abundance of distinct folded/misfolded forms of proinsulin using a novel nonreducing SDS‐PAGE/immunoblotting protocol. We confirm abundant proinsulin misfolding upon introduction of a diabetogenic INS mutation, or in the islets of db/db mice. Whereas blockade of proinsulin trafficking in Golgi/post‐Golgi compartments results in intracellular accumulation of properly‐folded proinsulin (bearing native disulfide bonds), impairment of ER‐to‐Golgi trafficking (regardless whether such impairment is achieved by genetic or pharmacologic means) results in decreased native proinsulin with more misfolded proinsulin. Remarkably, reversible ER‐to‐Golgi transport defects (such as treatment with brefeldin A or cellular energy depletion) upon reversal quickly restore the ER folding environment, resulting in the disappearance of pre‐existing misfolded proinsulin while preserving proinsulin bearing native disulfide bonds. Thus, proper homeostatic balance of ER‐to‐Golgi trafficking is linked to a more favorable proinsulin folding (as well as trafficking) outcome. [ABSTRACT FROM AUTHOR]

Published
2024
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24. Quantifying stem cell derived islet graft volume and composition with [18F]F-DBCO-exendin and [18F]FDOPA positron emission tomography

Author

Lithovius, Väinö, primary, Lahdenpohja, Salla, additional, Ibrahim, Hazem, additional, Saarimäki-Vire, Jonna, additional, Uusitalo, Lotta, additional, Montaser, Hossam, additional, Mikkola, Kirsi, additional, Yim, Cheng-Bin, additional, Keller, Thomas, additional, Rajander, Johan, additional, Balboa, Diego, additional, Barsby, Tom, additional, Solin, Olof, additional, Nuutila, Pirjo, additional, Grönroos, Tove J., additional, and Otonkoski, Timo, additional

Published
2023
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25. Loss of ZnT8 function protects against diabetes by enhanced insulin secretion

Author

Dwivedi, Om Prakash, Lehtovirta, Mikko, Hastoy, Benoit, Chandra, Vikash, Krentz, Nicole A. J., Kleiner, Sandra, Jain, Deepak, Richard, Ann-Marie, Abaitua, Fernando, Beer, Nicola L., Grotz, Antje, Prasad, Rashmi B., Hansson, Ola, Ahlqvist, Emma, Krus, Ulrika, Artner, Isabella, Suoranta, Anu, Gomez, Daniel, Baras, Aris, Champon, Benoite, Payne, Anthony J., Moralli, Daniela, Thomsen, Soren K., Kramer, Philipp, Spiliotis, Ioannis, Ramracheya, Reshma, Chabosseau, Pauline, Theodoulou, Andria, Cheung, Rebecca, van de Bunt, Martijn, Flannick, Jason, Trombetta, Maddalena, Bonora, Enzo, Wolheim, Claes B., Sarelin, Leena, Bonadonna, Riccardo C., Rorsman, Patrik, Davies, Benjamin, Brosnan, Julia, McCarthy, Mark I., Otonkoski, Timo, Lagerstedt, Jens O., Rutter, Guy A., Gromada, Jesper, Gloyn, Anna L., Tuomi, Tiinamaija, and Groop, Leif

Published
2019
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27. Aberrant metabolite trafficking and fuel sensitivity in human pluripotent stem cell-derived islets

Author

Barsby, Tom, primary, Vähäkangas, Eliisa, additional, Ustinov, Jarkko, additional, Montaser, Hossam, additional, Ibrahim, Hazem, additional, Lithovius, Väinö, additional, Kuuluvainen, Emilia, additional, Chandra, Vikash, additional, Saarimäki-Vire, Jonna, additional, Katajisto, Pekka, additional, Hietakangas, Ville, additional, and Otonkoski, Timo, additional

Published
2023
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28. Increased Frequency of the HLA-DRB1*04:04-DQA1*03-DQB1*03:02 Haplotype Among HLA-DQB1*06:02–Positive Children With Type 1 Diabetes.

Author

Ilonen, Jorma, Kiviniemi, Minna, El-Amir, Mostafa I., Nygård, Lucas, Härkönen, Taina, Lempainen, Johanna, Knip, Mikael, Finnish Pediatric Diabetes Register, Groop, Per-Henrik, Otonkoski, Timo, Veijola, Riitta, Abram, Alar, Aito, Henrikka, Arkhipov, Ivan, Blanco-Sequeiros, Elina, Bondestam, Jonas, Granholm, Markus, Haapalehto-Ikonen, Maarit, Horn, Torsten, and Huopio, Hanna

Subjects
TYPE 1 diabetes, HAPLOTYPES, DIABETES in children, GENE frequency, AUTOANTIBODIES
Abstract

HLA-DR/DQ haplotypes largely define genetic susceptibility to type 1 diabetes (T1D). The DQB1*06:02-positive haplotype (DR15-DQ602) common in individuals of European ancestry is very rare among children with T1D. Among 4,490 children with T1D in the Finnish Pediatric Diabetes Register, 57 (1.3%) case patients with DQB1*06:02 were identified, in comparison with 26.1% of affected family-based association control participants. There were no differences between DQB1*06:02-positive and -negative children with T1D regarding sex, age, islet autoantibody distribution, or autoantibody levels, but significant differences were seen in the frequency of second class II HLA haplotypes. The most prevalent haplotype present with DQB1*06:02 was DRB1*04:04-DQA1*03-DQB1*03:02, which was found in 27 (47.4%) of 57 children, compared with only 797 (18.0%) of 4,433 among DQB1*06:02-negative case patients (P < 0.001 by χ2 test). The other common risk-associated haplotypes, DRB1*04:01-DQA1*03-DQB1*03:02 and (DR3)-DQA1*05-DQB1*02, were less prevalent in DQB1*06:02-positive versus DQB1*06:02-negative children (P < 0.001). HLA-B allele frequencies did not differ by DQB1*06:02 haplotype between children with T1D and control participants or by DRB1*04:04-DQA1*03-DQB1*03:02 haplotype between DQB1*06:02-positive and -negative children with T1D. The increased frequency of the DRB1*04:04 allele among DQB1*06:02-positive case patients may indicate a preferential ability of the DR404 molecule to present islet antigen epitopes despite competition by DQ602. Article Highlights: The common HLA-DQB1*06:02 allele is strongly protective against type 1 diabetes (T1D), although few DQB1*06:02-positive individuals have been found. We compared the distribution of the second class II haplotypes in DQB1*06:02-positive children with T1D with the distribution of haplotypes found in in other children with T1D. HLA-DRB1*04:04-DQA1*03-DQB1*03:02 was the most common second haplotype in DQB1*06:02-positive children with T1D, whereas DRB1*04:01-DQA1*03-DQB1*03:02 was most frequent in other children with T1D. This finding suggests that the islet-specific epitopes presented by DRB1*04:04 can more efficiently avoid binding to DQB1*06:02 than epitopes presented by other risk-associated haplotypes. [ABSTRACT FROM AUTHOR]

Published
2024
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31. Gene expression signature predicts rate of type 1 diabetes progression

Author

Suomi, Tomi, primary, Starskaia, Inna, additional, Kalim, Ubaid Ullah, additional, Rasool, Omid, additional, Jaakkola, Maria K., additional, Grönroos, Toni, additional, Välikangas, Tommi, additional, Brorsson, Caroline, additional, Mazzoni, Gianluca, additional, Bruggraber, Sylvaine, additional, Overbergh, Lut, additional, Dunger, David, additional, Peakman, Mark, additional, Chmura, Piotr, additional, Brunak, Søren, additional, Schulte, Anke M., additional, Mathieu, Chantal, additional, Knip, Mikael, additional, Lahesmaa, Riitta, additional, Elo, Laura L., additional, Gillard, Pieter, additional, Casteels, Kristina, additional, Overbergh, Lutgart, additional, Wallace, Chris, additional, Evans, Mark, additional, Thankamony, Ajay, additional, Hendriks, Emile, additional, Marcoveccchio, Loredana, additional, Tree, Timothy, additional, Morgan, Noel G., additional, Richardson, Sarah, additional, Todd, John A., additional, Wicker, Linda, additional, Mander, Adrian, additional, Dayan, Colin, additional, Alhadj Ali, Mohammad, additional, Pieber, Thomas, additional, Eizirik, Decio L., additional, Cnop, Myriam, additional, Pociot, Flemming, additional, Johannesen, Jesper, additional, Rossing, Peter, additional, Quigley, Cristina Legido, additional, Mallone, Roberto, additional, Scharfmann, Raphael, additional, Boitard, Christian, additional, Otonkoski, Timo, additional, Veijola, Riitta, additional, Oresic, Matej, additional, Toppari, Jorma, additional, Danne, Thomas, additional, Ziegler, Anette G., additional, Achenbach, Peter, additional, Rodriguez-Calvo, Teresa, additional, Solimena, Michele, additional, Bonifacio, Ezio E., additional, Speier, Stephan, additional, Holl, Reinhard, additional, Dotta, Francesco, additional, Chiarelli, Francesco, additional, Marchetti, Piero, additional, Bosi, Emanuele, additional, Cianfarani, Stefano, additional, Ciampalini, Paolo, additional, De Beaufort, Carine, additional, Dahl-Jørgensen, Knut, additional, Skrivarhaug, Torild, additional, Joner, Geir, additional, Krogvold, Lars, additional, Jarosz-Chobot, Przemka, additional, Battelino, Tadej, additional, Thorens, Bernard, additional, Gotthardt, Martin, additional, Roep, Bart O., additional, Nikolic, Tanja, additional, Zaldumbide, Arnaud, additional, Lernmark, Ake, additional, Lundgren, Marcus, additional, Costacalde, Guillaume, additional, Strube, Thorsten, additional, Nitsche, Almut, additional, Vela, Jose, additional, Von Herrath, Matthias, additional, Wesley, Johnna, additional, Napolitano-Rosen, Antonella, additional, Thomas, Melissa, additional, Schloot, Nanette, additional, Goldfine, Allison, additional, Waldron-Lynch, Frank, additional, Kompa, Jill, additional, Vedala, Aruna, additional, Hartmann, Nicole, additional, Nicolas, Gwenaelle, additional, van Rampelbergh, Jean, additional, Bovy, Nicolas, additional, Dutta, Sanjoy, additional, Soderberg, Jeannette, additional, Ahmed, Simi, additional, Martin, Frank, additional, Latres, Esther, additional, Agiostratidou, Gina, additional, Koralova, Anne, additional, Willemsen, Ruben, additional, Smith, Anne, additional, Anand, Binu, additional, Datta, Vipan, additional, Puthi, Vijith, additional, Zac-Varghese, Sagen, additional, Dias, Renuka, additional, Sundaram, Premkumar, additional, Vaidya, Bijay, additional, Patterson, Catherine, additional, Owen, Katharine, additional, Piel, Barbara, additional, Heller, Simon, additional, Randell, Tabitha, additional, Gazis, Tasso, additional, Reismen, Elise Bismuth, additional, Carel, Jean-Claude, additional, Riveline, Jean-Pierre, additional, Gautier, Jean-Francoise, additional, Andreelli, Fabrizion, additional, Travert, Florence, additional, Cosson, Emmanuel, additional, Penfornis, Alfred, additional, Petit, Catherine, additional, Feve, Bruno, additional, Lucidarme, Nadine, additional, Beressi, Jean-Paul, additional, Ajzenman, Catherina, additional, Radu, Alina, additional, Greteau-Hamoumou, Stephanie, additional, Bibal, Cecile, additional, Meissner, Thomas, additional, Heidtmann, Bettina, additional, Toni, Sonia, additional, Rami-Merhar, Birgit, additional, Eeckhout, Bart, additional, Peene, Bernard, additional, Vantongerloo, N., additional, Maes, Toon, additional, and Gommers, Leen, additional

Published
2023
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33. Publisher Correction: Pharmacological reactivation of MYC-dependent apoptosis induces susceptibility to anti-PD-1 immunotherapy

Author

Haikala, Heidi M., Anttila, Johanna M., Marques, Elsa, Raatikainen, Tiina, Ilander, Mette, Hakanen, Henna, Ala-Hongisto, Hanna, Savelius, Mariel, Balboa, Diego, Von Eyss, Bjoern, Eskelinen, Vilja, Munne, Pauliina, Nieminen, Anni I., Otonkoski, Timo, Schüler, Julia, Laajala, Teemu D., Aittokallio, Tero, Sihto, Harri, Mattson, Johanna, Heikkilä, Päivi, Leidenius, Marjut, Joensuu, Heikki, Mustjoki, Satu, Kovanen, Panu, Eilers, Martin, Leverson, Joel D., and Klefström, Juha

Published
2019
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34. Pharmacological reactivation of MYC-dependent apoptosis induces susceptibility to anti-PD-1 immunotherapy

Author

Haikala, Heidi M., Anttila, Johanna M., Marques, Elsa, Raatikainen, Tiina, Ilander, Mette, Hakanen, Henna, Ala-Hongisto, Hanna, Savelius, Mariel, Balboa, Diego, Von Eyss, Bjoern, Eskelinen, Vilja, Munne, Pauliina, Nieminen, Anni I., Otonkoski, Timo, Schüler, Julia, Laajala, Teemu D., Aittokallio, Tero, Sihto, Harri, Mattson, Johanna, Heikkilä, Päivi, Leidenius, Marjut, Joensuu, Heikki, Mustjoki, Satu, Kovanen, Panu, Eilers, Martin, Leverson, Joel D., and Klefström, Juha

Published
2019
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40. Autoimmunity, hypogammaglobulinemia, lymphoproliferation, and mycobacterial disease in patients with activating mutations in STAT3

Author

Haapaniemi, Emma M., Kaustio, Meri, Rajala, Hanna L.M., van Adrichem, Arjan J., Kainulainen, Leena, Glumoff, Virpi, Doffinger, Rainer, Kuusanmäki, Heikki, Heiskanen-Kosma, Tarja, Trotta, Luca, Chiang, Samuel, Kulmala, Petri, Eldfors, Samuli, Katainen, Riku, Siitonen, Sanna, Karjalainen-Lindsberg, Marja-Liisa, Kovanen, Panu E., Otonkoski, Timo, Porkka, Kimmo, Heiskanen, Kaarina, Hänninen, Arno, Bryceson, Yenan T., Uusitalo-Seppälä, Raija, Saarela, Janna, Seppänen, Mikko, Mustjoki, Satu, and Kere, Juha

Published
2015
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41. In vitro beta-cell killing models using immune cells and human pluripotent stem cell-derived islets : Challenges and opportunities

Author

Halliez, Clementine, Ibrahim, Hazem, Otonkoski, Timo, Mallone, Roberto, Research Programs Unit, STEMM - Stem Cells and Metabolism Research Program, Centre of Excellence in Stem Cell Metabolism, Helsinki One Health (HOH), HUS Children and Adolescents, Clinicum, Timo Pyry Juhani Otonkoski / Principal Investigator, Children's Hospital, and University of Helsinki

Subjects
Beta-cells, human leukocyte antigen (HLA), Type 1 diabetes, T-cells, Cytotoxicity, Stem-cell-derived islets, iPSCs, 3111 Biomedicine
Abstract

Type 1 diabetes (T1D) is a disease of both autoimmunity and beta-cells. The beta-cells play an active role in their own demise by mounting defense mechanisms that are insufficient at best, and that can become even deleterious in the long term. This complex crosstalk is important to understanding the physiological defense mechanisms at play in healthy conditions, their alterations in the T1D setting, and therapeutic agents that may boost such mechanisms. Robust protocols to develop stem-cell-derived islets (SC-islets) from human pluripotent stem cells (hPSCs), and islet-reactive cytotoxic CD8(+) T-cells from peripheral blood mononuclear cells offer unprecedented opportunities to study this crosstalk. Challenges to develop in vitro beta-cell killing models include the cluster morphology of SC-islets, the relatively weak cytotoxicity of most autoimmune T-cells and the variable behavior of in vitro expanded CD8(+) T-cells. These challenges may however be highly rewarding in light of the opportunities offered by such models. Herein, we discuss these opportunities including: the beta-cell/immune crosstalk in an islet microenvironment; the features that make beta-cells more sensitive to autoimmunity; therapeutic agents that may modulate beta-cell vulnerability; and the possibility to perform analyses in an autologous setting, i.e., by generating T-cell effectors and SC-islets from the same donor.

Published
2023

44. Islet Gene View—a tool to facilitate islet research

Author

Asplund, Olof, primary, Storm, Petter, additional, Chandra, Vikash, additional, Hatem, Gad, additional, Ottosson-Laakso, Emilia, additional, Mansour-Aly, Dina, additional, Krus, Ulrika, additional, Ibrahim, Hazem, additional, Ahlqvist, Emma, additional, Tuomi, Tiinamaija, additional, Renström, Erik, additional, Korsgren, Olle, additional, Wierup, Nils, additional, Ibberson, Mark, additional, Solimena, Michele, additional, Marchetti, Piero, additional, Wollheim, Claes, additional, Artner, Isabella, additional, Mulder, Hindrik, additional, Hansson, Ola, additional, Otonkoski, Timo, additional, Groop, Leif, additional, and Prasad, Rashmi B, additional

Published
2022
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47. PTPN2 Regulates the Interferon Signaling and Endoplasmic Reticulum Stress Response in Pancreatic β-Cells in Autoimmune Diabetes

Author

Elvira, Bernat, Vandenbempt, Valerie, Bauzá-Martinez, Julia, Crutzen, Raphaël, Negueruela, Javier, Ibrahim, Hazem, Winder, Matthew L., Brahma, Manoja K., Vekeriotaite, Beata, Martens, Pieter Jan, Singh, Sumeet Pal, Rossello, Fernando, Lybaert, Pascale, Otonkoski, Timo, Gysemans, Conny, Wu, Wei, Gurzov, Esteban N., Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Afd Biomol.Mass Spect. and Proteomics, and Biomolecular Mass Spectrometry and Proteomics

Subjects
Protein Tyrosine Phosphatase, Non-Receptor Type 2, Protein Tyrosine Phosphatase, Non-Receptor Type 2/genetics, Endocrinology, Diabetes and Metabolism, Apoptosis, Type 1/metabolism, Interferon-gamma/pharmacology, Endoplasmic Reticulum Stress/physiology, Endoplasmic Reticulum Stress, Non-Receptor Type 2/genetics, Diabetes and Metabolism, Interferon-gamma, Mice, Diabetes Mellitus, Type 1, Endocrinology, Insulin-Secreting Cells/metabolism, Mice, Inbred NOD, Insulin-Secreting Cells, Apoptosis/genetics, Diabetes Mellitus, Internal Medicine, Inbred NOD, Animals, Diabetes Mellitus, Type 1/metabolism, Humans, Protein Tyrosine Phosphatase
Abstract

Type 1 diabetes (T1D) results from autoimmune destruction of β-cells in the pancreas. Protein tyrosine phosphatases (PTPs) are candidate genes for T1D and play a key role in autoimmune disease development and β-cell dysfunction. Here, we assessed the global protein and individual PTP profiles in the pancreas from early onset non-obese diabetic (NOD) mice treated with an anti-CD3 monoclonal antibody and interleukin-1 receptor antagonist. The treatment reversed hyperglycemia and we observed enhanced expression of PTPN2, a PTP family member and T1D candidate gene, and endoplasmic reticulum (ER) chaperones in the pancreatic islets. To address the functional role of PTPN2 in β-cells, we generated PTPN2-deficient human stem cell-derived β-like and EndoC-βH1 cells. Mechanistically, we demonstrated that PTPN2 inactivation in β-cells exacerbates type I and type II interferon signaling networks and the potential progression towards autoimmunity. Moreover, we established the capacity of PTPN2 to positively modulate the Ca2+-dependent unfolded protein response and ER stress outcome in β-cells. Adenovirus-induced overexpression of PTPN2 partially protected from ER-stress induced β-cell death. Our results postulate PTPN2 as a key protective factor in β-cells during inflammation and ER stress in autoimmune diabetes.

Published
2022

48. Islet Gene View-a tool to facilitate islet research

Author

Asplund, Olof, Storm, Petter, Chandra, Vikash, Hatem, Gad, Ottosson-Laakso, Emilia, Mansour-Aly, Dina, Krus, Ulrika, Ibrahim, Hazem, Ahlqvist, Emma, Tuomi, Tiinamaija, Renström, Erik, Korsgren, Olle, Wierup, Nils, Ibberson, Mark, Solimena, Michele, Marchetti, Piero, Wollheim, Claes, Artner, Isabella, Mulder, Hindrik, Hansson, Ola, Otonkoski, Timo, Groop, Leif, Prasad, Rashmi B., Asplund, Olof, Storm, Petter, Chandra, Vikash, Hatem, Gad, Ottosson-Laakso, Emilia, Mansour-Aly, Dina, Krus, Ulrika, Ibrahim, Hazem, Ahlqvist, Emma, Tuomi, Tiinamaija, Renström, Erik, Korsgren, Olle, Wierup, Nils, Ibberson, Mark, Solimena, Michele, Marchetti, Piero, Wollheim, Claes, Artner, Isabella, Mulder, Hindrik, Hansson, Ola, Otonkoski, Timo, Groop, Leif, and Prasad, Rashmi B.

Abstract

Characterization of gene expression in pancreatic islets and its alteration in type 2 diabetes (T2D) are vital in understanding islet function and T2D pathogenesis. We leveraged RNA sequencing and genome-wide genotyping in islets from 188 donors to create the Islet Gene View (IGW) platform to make this information easily accessible to the scientific community. Expression data were related to islet phenotypes, diabetes status, other islet-expressed genes, islet hormone-encoding genes and for expression in insulin target tissues. The IGW web application produces output graphs for a particular gene of interest. In IGW, 284 differentially expressed genes (DEGs) were identified in T2D donor islets compared with controls. Forty percent of DEGs showed cell-type enrichment and a large proportion significantly co-expressed with islet hormone-encoding genes; glucagon (GCG, 56%), amylin (IAPP, 52%), insulin (INS, 44%), and somatostatin (SST, 24%). Inhibition of two DEGs, UNC5D and SERPINE2, impaired glucose-stimulated insulin secretion and impacted cell survival in a human beta-cell model. The exploratory use of IGW could help designing more comprehensive functional follow-up studies and serve to identify therapeutic targets in T2D.

Published
2022
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50. Chromatin remodeler developmental pluripotency associated factor 4 (DPPA4) is a candidate gene for alcohol-induced developmental disorders

Author

Auvinen, Pauliina, primary, Vehviläinen, Jussi, additional, Marjonen, Heidi, additional, Modhukur, Vijayachitra, additional, Sokka, Joonas, additional, Wallén, Essi, additional, Rämö, Karita, additional, Ahola, Laura, additional, Salumets, Andres, additional, Otonkoski, Timo, additional, Skottman, Heli, additional, Ollikainen, Miina, additional, Trokovic, Ras, additional, Kahila, Hanna, additional, and Kaminen-Ahola, Nina, additional

Published
2022
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