Author "Otonkoski, Timo"

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1. Maturation of beta cells: lessons from in vivo and in vitro models [2022]

  • Barsby, Tom and Otonkoski, Timo
  • Diabetologia. June, 2022, Vol. 65 Issue 6, p917, 14 p.

2. Genome editing of human pancreatic beta cell models : problems, possibilities and outlook [2019]

  • Balboa, Diego, Prasad, Rashmi B, Groop, Leif, and Otonkoski, Timo
  • Diabetologia EXODIAB: Excellence of Diabetes Research in Sweden. 62(8):1329-1336
Subjects
Medicin och hälsovetenskap, Klinisk medicin, Endokrinologi och diabetes, Medical and Health Sciences, Clinical Medicine, Endocrinology and Diabetes, Medicinska och farmaceutiska grundvetenskaper, Cell- och molekylärbiologi, Basic Medicine, and Cell and Molecular Biology
Abstract
Understanding the molecular mechanisms behind beta cell dysfunction is essential for the development of effective and specific approaches for diabetes care and prevention. Physiological human beta cell models are needed for this work. We review the possibilities and limitations of currently available human beta cell models and how they can be dramatically enhanced using genome-editing technologies. In addition to the gold standard, primary isolated islets, other models now include immortalised human beta cell lines and pluripotent stem cell-derived islet-like cells. The scarcity of human primary islet samples limits their use, but valuable gene expression and functional data from large collections of human islets have been made available to the scientific community. The possibilities for studying beta cell physiology using immortalised human beta cell lines and stem cell-derived islets are rapidly evolving. However, the functional immaturity of these cells is still a significant limitation. CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9) has enabled precise engineering of specific genetic variants, targeted transcriptional modulation and genome-wide genetic screening. These approaches can now be exploited to gain understanding of the mechanisms behind coding and non-coding diabetes-associated genetic variants, allowing more precise evaluation of their contribution to diabetes pathogenesis. Despite all the progress, genome editing in primary pancreatic islets remains difficult to achieve, an important limitation requiring further technological development.

3. Steroidogenic factor 1 (NR5A1) induces multiple transcriptional changes during differentiation of human gonadal-like cells [2022]

  • Sepponen, Kirsi, Lundin, Karolina, Yohannes, Dawit A., Vuoristo, Sanna, Balboa, Diego, Poutanen, Matti, Ohlsson, Claes, Hustad, Steinar, Bifulco, Ersilia, Paloviita, Pauliina, Otonkoski, Timo, Ritvos, Olli, Sainio, Kirsi, Tapanainen, Juha S., and Tuuri, Timo
  • In Differentiation November-December 2022 128:83-100

4. Transient DUX4 expression in human embryonic stem cells induces blastomere-like expression program that is marked by SLC34A2 [2022]

  • Yoshihara, Masahito, Kirjanov, Ida, Nykänen, Sonja, Sokka, Joonas, Weltner, Jere, Lundin, Karolina, Gawriyski, Lisa, Jouhilahti, Eeva-Mari, Varjosalo, Markku, Tervaniemi, Mari H., Otonkoski, Timo, Trokovic, Ras, Katayama, Shintaro, Vuoristo, Sanna, and Kere, Juha
  • Stem cell reports. 17(7):1743-1756

5. CRISPR activation enables high-fidelity reprogramming into human pluripotent stem cells [2022]

  • Sokka, Joonas, Yoshihara, Masahito, Kvist, Jouni, Laiho, Laura, Warren, Andrew, Stadelmann, Christian, Jouhilahti, Eeva-Mari, Kilpinen, Helena, Balboa, Diego, Katayama, Shintaro, Kyttälä, Aija, Kere, Juha, Otonkoski, Timo, Weltner, Jere, and Trokovic, Ras
  • Stem cell reports. 17(2):413-426

6. DUX4 is a multifunctional factor priming human embryonic genome activation [2022]

  • Vuoristo, Sanna, Bhagat, Shruti, Hydén-Granskog, Christel, Yoshihara, Masahito, Gawriyski, Lisa, Jouhilahti, Eeva-Mari, Ranga, Vipin, Tamirat, Mahlet, Huhtala, Mikko, Kirjanov, Ida, Nykänen, Sonja, Krjutškov, Kaarel, Damdimopoulos, Anastassius, Weltner, Jere, Hashimoto, Kosuke, Recher, Gaëlle, Ezer, Sini, Paluoja, Priit, Paloviita, Pauliina, Takegami, Yujiro, Kanemaru, Ai, Lundin, Karolina, Airenne, Tomi T., Otonkoski, Timo, Tapanainen, Juha S., Kawaji, Hideya, Murakawa, Yasuhiro, Bürglin, Thomas R., Varjosalo, Markku, Johnson, Mark S., Tuuri, Timo, Katayama, Shintaro, and Kere, Juha
  • In iScience 15 April 2022 25(4)

7. Functional, metabolic and transcriptional maturation of human pancreatic islets derived from stem cells. [2022]

  • 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
  • Nature Biotechnology.
Subjects
Medical and Health Sciences, Basic Medicine, Cell and Molecular Biology, Medicin och hälsovetenskap, Medicinska och farmaceutiska grundvetenskaper, Cell- och molekylärbiologi, Clinical Medicine, Endocrinology and Diabetes, Klinisk medicin, and Endokrinologi och diabetes
Abstract
Transplantation of pancreatic islet cells derived from human pluripotent stem cells is a promising treatment for diabetes. Despite progress in the generation of stem-cell-derived islets (SC-islets), no detailed characterization of their functional properties has been conducted. Here, we generated functionally mature SC-islets using an optimized protocol and benchmarked them comprehensively against primary adult islets. Biphasic glucose-stimulated insulin secretion developed during in vitro maturation, associated with cytoarchitectural reorganization and the increasing presence of alpha cells. Electrophysiology, signaling and exocytosis of SC-islets were similar to those of adult islets. Glucose-responsive insulin secretion was achieved despite differences in glycolytic and mitochondrial glucose metabolism. Single-cell transcriptomics of SC-islets in vitro and throughout 6 months of engraftment in mice revealed a continuous maturation trajectory culminating in a transcriptional landscape closely resembling that of primary islets. Our thorough evaluation of SC-islet maturation highlights their advanced degree of functionality and supports their use in further efforts to understand and combat diabetes.

8. PTPN2 Regulates the Interferon Signaling and Endoplasmic Reticulum Stress Response in Pancreatic [beta]-Cells in Autoimmune Diabetes [2022]

  • Elvira, Bernat, Vandenbempt, Valerie, Bauza-Martinez, Julia, Crutzen, Raphael, 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, and Gurzov, Esteban N.
  • Diabetes. April, 2022, Vol. 71 Issue 4, p653, 16 p.

9. Simultaneous high-efficiency base editing and reprogramming of patient fibroblasts [2021]

  • Jalil, Sami, Keskinen, Timo, Maldonado, Rocío, Sokka, Joonas, Trokovic, Ras, Otonkoski, Timo, and Wartiovaara, Kirmo
  • In Stem Cell Reports 14 December 2021 16(12):3064-3075

10. Genetic Variability Overrides the Impact of Parental Cell Type and Determines iPSC Differentiation Potential. [2016]

  • Kyttälä, Aija, Moraghebi, Roksana, Valensisi, Cristina, Kettunen, Johannes, Andrus, Colin, Pasumarthy, Kalyan Kumar, Nakanishi, Mahito, Nishimura, Ken, Ohtaka, Manami, Weltner, Jere, Van Handel, Ben, Parkkonen, Olavi, Sinisalo, Juha, Jalanko, Anu, Hawkins, R David, Woods, Niels-Bjarne, Otonkoski, Timo, and Trokovic, Ras
  • Stem Cell Reports StemTherapy: National Initiative on Stem Cells for Regenerative Therapy. 6(2):200-212
Subjects
Medicin och hälsovetenskap, Medicinska och farmaceutiska grundvetenskaper, Cell- och molekylärbiologi, Medical and Health Sciences, Basic Medicine, and Cell and Molecular Biology
Abstract
Reports on the retention of somatic cell memory in induced pluripotent stem cells (iPSCs) have complicated the selection of the optimal cell type for the generation of iPSC biobanks. To address this issue we compared transcriptomic, epigenetic, and differentiation propensities of genetically matched human iPSCs derived from fibroblasts and blood, two tissues of the most practical relevance for biobanking. Our results show that iPSC lines derived from the same donor are highly similar to each other. However, genetic variation imparts a donor-specific expression and methylation profile in reprogrammed cells that leads to variable functional capacities of iPSC lines. Our results suggest that integration-free, bona fide iPSC lines from fibroblasts and blood can be combined in repositories to form biobanks. Due to the impact of genetic variation on iPSC differentiation, biobanks should contain cells from large numbers of donors.

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12. Long-Term Outcome and Treatment in Persistent and Transient Congenital Hyperinsulinism: A Finnish Population-Based Study [2021]

  • Männistö, Jonna M E, Jääskeläinen, Jarmo, Otonkoski, Timo, and Huopio, Hanna
  • Journal of clinical endocrinology & metabolism. 106(4):1542-1551

13. SUR1-mutant iPS cell-derived islets recapitulate the pathophysiology of congenital hyperinsulinism [2021]

  • Lithovius, Väinö, Saarimäki-Vire, Jonna, Balboa, Diego, Ibrahim, Hazem, Montaser, Hossam, Barsby, Tom, and Otonkoski, Timo
  • Diabetologia: Clinical, Translational and Experimental Diabetes and Metabolism. 64(3):630-640

14. ALS and Parkinson's disease genes CHCHD10 and CHCHD2 modify synaptic transcriptomes in human iPSC-derived motor neurons [2020]

  • Harjuhaahto, Sandra, Rasila, Tiina S., Molchanova, Svetlana M., Woldegebriel, Rosa, Kvist, Jouni, Konovalova, Svetlana, Sainio, Markus T., Pennonen, Jana, Torregrosa-Muñumer, Rubén, Ibrahim, Hazem, Otonkoski, Timo, Taira, Tomi, Ylikallio, Emil, and Tyynismaa, Henna
  • In Neurobiology of Disease July 2020 141

15. Long-Term Outcome and Treatment in Persistent and Transient Congenital Hyperinsulinism: A Finnish Population-Based Study [2021]

  • Mannisto, Jonna M.E., Jaaskelainen, Jarmo, Otonkoski, Timo, and Huopio, Hanna
  • Journal of Clinical Endocrinology & Metabolism. April, 2021, Vol. 106 Issue 4, p1542, 10 p.

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17. Characterization of neural crest-derived stem cells isolated from human bone marrow for improvement of transplanted islet function. [2019]

  • Brboric, Anja, Vasylovska, Svitlana, Saarimäki-Vire, Jonna, Espes, Daniel, Caballero-Corbalán, José, Larfors, Gunnar, Otonkoski, Timo, and Lau, Joey
  • EXODIAB (Excellence of Diabetes Research in Sweden) Upsala Journal of Medical Sciences. 124(4):228-237
Subjects
Medical and Health Sciences, Basic Medicine, Cell and Molecular Biology, Medicin och hälsovetenskap, Medicinska och farmaceutiska grundvetenskaper, Cell- och molekylärbiologi, Adult bone marrow, diabetes, islet transplantation, neural crest stem cells, and pluripotent stem cells
Abstract
Background: Murine boundary cap-derived neural crest stem cells (NCSCs) are capable of enhancing islet function by stimulating beta cell proliferation as well as increasing the neural and vascular density in the islets both in vitro and in vivo. This study aimed to isolate NCSC-like cells from human bone marrow.Methods: CD271 magnetic cell separation and culture techniques were used to purify a NCSC-enriched population of human bone marrow. Analyses of the CD271+ and CD271- fractions in terms of protein expression were performed, and the capacity of the CD271+ bone marrow cells to form 3-dimensional spheres when grown under non-adherent conditions was also investigated. Moreover, the NCSC characteristics of the CD271+ cells were evaluated by their ability to migrate toward human islets as well as human islet-like cell clusters (ICC) derived from pluripotent stem cells.Results: The CD271+ bone marrow population fulfilled the criterion of being multipotent stem cells, having the potential to differentiate into glial cells, neurons as well as myofibroblasts in vitro. They had the capacity to form 3-dimensional spheres as well as an ability to migrate toward human islets, further supporting their NCSC identity. Additionally, we demonstrated similar migration features toward stem cell-derived ICC.Conclusion: The results support the NCSC identity of the CD271-enriched human bone marrow population. It remains to investigate whether the human bone marrow-derived NCSCs have the ability to improve transplantation efficacy of not only human islets but stem cell-derived ICC as well.

18. YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress [2020]

  • 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.
  • Journal of Clinical Investigation. Dec 2020, Vol. 130 Issue 12, p6338, 16 p.

19. Loss of ZnT8 function protects against diabetes by enhanced insulin secretion [2019]

  • 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
  • Nature Genetics EXODIAB: Excellence of Diabetes Research in Sweden StemTherapy: National Initiative on Stem Cells for Regenerative Therapy. :1-22
Subjects
Medicin och hälsovetenskap, Medicinska och farmaceutiska grundvetenskaper, Medicinsk genetik, Medical and Health Sciences, Basic Medicine, Medical Genetics, Klinisk medicin, Endokrinologi och diabetes, Clinical Medicine, and Endocrinology and Diabetes
Abstract
A rare loss-of-function allele p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8), which is enriched in Western Finland, protects against type 2 diabetes (T2D). We recruited relatives of the identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness and proinsulin conversion, particularly when compared with individuals matched for the genotype of a common T2D-risk allele in SLC30A8, p.Arg325. In genome-edited human induced pluripotent stem cell (iPSC)-derived β-like cells, we establish that the p.Arg138* allele results in reduced SLC30A8 expression due to haploinsufficiency. In human β cells, loss of SLC30A8 leads to increased glucose responsiveness and reduced KATP channel function similar to isolated islets from carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for treatment aimed at maintaining insulin secretion capacity in T2D.

20. Loss of MANF Causes Childhood-Onset Syndromic Diabetes Due to Increased Endoplasmic Reticulum Stress [2021]

  • Montaser, Hossam, Patel, Kashyap A., Balboa, Diego, Ibrahim, Hazem, Lithovius, Vaino, Naatanen, Anna, Chandra, Vikash, Demir, Korcan, Acar, Sezer, Ben-Omran, Tawfeg, Colclough, Kevin, Locke, Jonathan M., Wakeling, Matthew, Lindahl, Maria, Hattersley, Andrew T., Saarimaki-Vire, Jonna, and Otonkoski, Timo
  • Diabetes. April 2021, Vol. 70 Issue 4, p1006, 13 p.

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