My research aims at studying the molecular switches acting as regenerative or cell-plasticity breaks by actively maintaining the cell fate, thereby ensuring the strict regulation of cell identity and/or numbers.

Currently, we are focusing on metabolic and immune players, which we recently identified to be involved in the emergence of the immediate neoplastic transformation signature in a model of bladder cancer. We intend to resolve the causal relationship and contribution to mechanisms regulating cell fate and tumour development by abolishing or augmenting their impact, with the final goal of aborting early neoplastic transformation.

Previously, by using genetic cell fate-tracing techniques, I studied a spontaneous age-dependent regeneration process in the mammalian pancreas, based on a cell-fate conversion. Although a natural attempt of mammalian regeneration, this regenerative mechanism was extremely inefficient, with only 2% of the cells converting at any given time point (Thorel et al., Nature, 2010; Chera et al. Nature, 2014). We investigated the cellular and molecular mechanisms behind this restricted cell identity change and revealed that Insulin and Hedgehog signalling pathways act as natural cell-plasticity breaks by actively maintaining cell-identity (Cigliola*, Ghila*, Thorel* et al., Nature Cell Biology, 2018; *equal contribution). These results are neither organ-specific nor isolated, with an incremental body of literature reporting cell-plasticity breaks in many mammalian tissue and organs. Several recent studies pointed towards a short list of signalling pathways involved, reviewed by us in Cigliola, Ghila et al., 2020, Stem Cells. 

I am currently investigating the molecular mechanisms acting during cell reprogramming and differentiation using mouse models and hiPS-derived human cell models.  

ELMED303 Future medicine

LAS302 Mammal Science Course

Lecture

• Legøy, Thomas Aga; Mathisen, Andreas Frøslev; Paulo, Joao et al. (2024). Impact of endocrine disruptors on MODY3 iPSCs differentiation toward SC-islets – potential diabetogens. (external link)
• Legøy, Thomas Aga; Mathisen, Andreas Frøslev; Paulo, Joao et al. (2024). Impact of diabetogenic signals from endocrine disrupting chemicals on a HNF1A cell model. (external link)
• Mathisen, Andreas Frøslev; Legøy, Thomas Aga; Larsen, Ulrik et al. (2023). Hnf1a Is An Important Regulator in Ageing And Maturation Of Pancreatic Islets. (external link)
• Unger, Lucas; Legøy, Thomas Aga; Ghila, Luiza Mihaela et al. (2023). Exploring the role of transcription factors HNF1A, HNF1B, and HNF4A in human induced pluripotent stem cell-derived pancreatic islet cell differentiation. (external link)
• Unger, Lucas; Legøy, Thomas Aga; Chera, Simona et al. (2023). Exploring the role of transcription factors HNF1A, HNF1B, and HNF4A in human pancreatic islet cell differentiation. (external link)
• Ghila, Luiza Mihaela (2022). Chronically Elevated Exogenous Glucose Elicits Antipodal Effects on the Proteome Signature of Differentiating Human iPSC-Derived Pancreatic Progenitors. (external link)
• Ghila, Luiza Mihaela (2022). Mapping tumour heterogeneity and predictive cancer signatures in vivo. (external link)

Poster

• Sharmine, Shayla; Ghila, Luiza Mihaela; Chera, Simona (2024). Short-term effect of Somatostatin Modulators on Glycemic Control in MODY mice. (external link)
• Unger, Lucas; Legøy, Thomas Aga; Ghila, Luiza Mihaela et al. (2024). Exploring hedgehog signaling and HNF1A Crosstalk in HNF1A-MODY stem cell islets. (external link)
• Unger, Lucas; Mathisen, Andreas Frøslev; Legøy, Thomas Aga et al. (2024). Deciphering the HNF1A and Hedgehog Signaling Crosstalk during Stem Cell Islet differentiation. (external link)
• Hossain, Md Kaykobad; Altankhuyag, Altanchimeg; Legøy, Thomas Aga et al. (2023). Mapping predictive bladder cancer signatures in a mouse model. (external link)
• Legøy, Thomas Aga; Mathisen, Andreas Frøslev; Paulo, Joao et al. (2023). Human induced pluripotent stem cells as a model for environmental impact on diabetes. (external link)
• Sharmine, Shayla; Legøy, Thomas Aga; Mathisen, Andreas Frøslev et al. (2023). Mapping islet architecture changes upon high fat diet challenge in a HNF1A-MODY mouse model. (external link)
• Unger, Lucas; Legøy, Thomas Aga; Mathisen, Andreas Frøslev et al. (2023). Investigating the developmental role of HNF1A, HNF1B and HNF4A in human pancreatic islet cell differentiation. (external link)
• Mathisen, Andreas Frøslev; Legøy, Thomas Aga; Ghila, Luiza Mihaela et al. (2022). Know your background, know your data. (external link)
• Legøy, Thomas Aga; Mathisen, Andreas Frøslev; Scholz, Hanne et al. (2022). Molecular mechanisms affecting islet like cell fate acquisition in differentiating iPSC derived β-like cells”. (external link)
• Mathisen, Andreas Frøslev; Legøy, Thomas Aga; Ghila, Luiza Mihaela et al. (2022). Mind your background!. (external link)
• Mathisen, Andreas Frøslev; Legøy, Thomas Aga; Ghila, Luiza Mihaela et al. (2022). Hnf1a is a key regulator of β-cell identity and function. (external link)
• Unger, Lucas; Legøy, Thomas Aga; Ghila, Luiza Mihaela et al. (2022). Investigating the developmental role of HNF1A in human pancreatic islet cell differentiation. (external link)
• Unger, Lucas; Ghila, Luiza Mihaela; Chera, Simona (2022). Investigating the developmental role of HNF1A, HNF1B and HNF4A in human pancreatic islet cell differentiation. (external link)
• Wang, Chencheng; Abadpour, Shadab; Aizenshtadt, Alexandra et al. (2021). Glucose during in vitro pancreatic beta cells regeneration: friends or for?. (external link)

Academic article

• Unger, Lucas; Ghila, Luiza Mihaela; Chera, Simona (2024). Targeted Gene Silencing by Using GapmeRs in Differentiating Human-Induced Pluripotent Stem Cells (hiPSC) Toward Pancreatic Progenitors. (external link)
• Mathisen, Andreas Frøslev; Vacaru, Andrei Mircea; Unger, Lucas et al. (2024). Molecular profiling of NOD mouse islets reveals a novel regulator of insulitis onset. (external link)
• Wang, Chencheng; Abadpour, Shadab; Olsen, Petter Angell et al. (2024). Glucose Concentration in Regulating Induced Pluripotent Stem Cells Differentiation Toward Insulin-Producing Cells. (external link)
• Mathisen, Andreas Frøslev; Legøy, Thomas Aga; Larsen, Ulrik et al. (2024). The age-dependent regulation of pancreatic islet landscape is fueled by a HNF1a-immune signaling loop. (external link)
• Wang, Chencheng; Abadpour, Shadab; Aizenshtadt, Aleksandra et al. (2024). Cell identity dynamics and insight into insulin secretagogues when employing stem cell-derived islets for disease modeling. (external link)
• Mathisen, Andreas Frøslev; Larsen, Ulrik; Kavli, Natalie Aasen et al. (2024). Moderate beta-cell ablation triggers synergic compensatory mechanisms even in the absence of overt metabolic disruption. (external link)
• Mathisen, Andreas Frøslev; Vacaru, Andrei Mircea; Unger, Lucas et al. (2024). Molecular profiling of NOD mouse islets reveals a novel regulator of insulitis onset.. (external link)
• Unger, Lucas; Mathisen, Andreas Frøslev; Chera, Simona et al. (2024). The GLI code controls HNF1A levels during foregut differentiation. (external link)
• Mathisen, Andreas Frøslev; Larsen, Ulrik; Kavli, Natalie Aasen et al. (2024). Moderate beta-cell ablation triggers synergic compensatory mechanisms even in the absence of overt metabolic disruption. (external link)
• Mathisen, Andreas Frøslev; Legøy, Thomas Aga; Larsen, Ulrik et al. (2024). The age-dependent regulation of pancreatic islet landscape is fueled by a HNF1a-immune signaling loop. . (external link)
• Daian, Laura Maria; Tanko, Gabriela; Vacaru, Andrei Mircea et al. (2023). Modulation of Unfolded Protein Response Restores Survival and Function of β-Cells Exposed to the Endocrine Disruptor Bisphenol A. (external link)
• Mathisen, Andreas Frøslev; Abadpour, Shadab; Legøy, Thomas Aga et al. (2023). Global proteomics reveals insulin abundance as a marker of human islet homeostasis alterations. (external link)
• Fernandez, Manuel Carrasco; Wang, Chencheng; Søviknes, Anne Mette et al. (2022). Spatial Environment Affects HNF4A Mutation-Specific Proteome Signatures and Cellular Morphology in hiPSC-Derived β-Like Cells. (external link)
• Bhagchandani, Preksha; Chang, Charles A.; Zhao, Weichen et al. (2022). Islet cell replacement and transplantation immunology in a mouse strain with inducible diabetes. (external link)
• Ghila, Luiza; Legøy, Thomas Aga; Mathisen, Andreas Frøslev et al. (2021). Chronically elevated exogenous glucose elicits antipodal effects on the proteome signature of differentiating human ipsc-derived pancreatic progenitors. (external link)
• Ghila, Luiza; Legøy, Thomas Aga; Chera, Simona (2021). A Method for Encapsulation and Transplantation into Diabetic Mice of Human Induced Pluripotent Stem Cells (hiPSC)-Derived Pancreatic Progenitors. (external link)
• Legøy, Thomas Aga; Vethe, Heidrun; Abadpour, Shadab et al. (2020). Encapsulation boosts islet-cell signature in differentiating human induced pluripotent stem cells via integrin signalling . (external link)
• Ghila, Luiza; Bjørlykke, Yngvild; Legøy, Thomas Aga et al. (2020). Bioinformatic analyses of miRNA-mRNA signature during hiPSC differentiation towards insulin-producing cells upon HNF4α mutation. (external link)
• Legøy, Thomas Aga; Mathisen, Andreas Frøslev; Salim, Zaidon et al. (2020). In vivo environment swiftly restricts human pancreatic progenitors toward mono-hormonal identity via a HNF1A/HNF4A mechanism. (external link)
• Legøy, Thomas Aga; Ghila, Luiza; Vethe, Heidrun et al. (2019). In vivo hyperglycemia exposure elicits distinct period-dependent effects on human pancreatic progenitor differentiation, conveyed by oxidative stress. (external link)
• Furuyama, Kenichiro; Chera, Simona; van Gurp, Leon et al. (2019). Diabetes relief in mice by glucose-sensing insulin-secreting human α-cells. (external link)
• Vethe, Heidrun; Legøy, Thomas Aga; Abadpour, Shadab et al. (2019). Encapsulation boosts islet-cell signature in differentiating human induced pluripotent stem cells via integrin signalling. (external link)
• Bjørlykke, Yngvild; Søviknes, Anne Mette; Hoareau, Laurence et al. (2019). Reprogrammed cells display distinct proteomic signaturesAssociated with colony morphology variability. (external link)
• Vethe, Heidrun; Ghila, Luiza; Berle, Magnus et al. (2019). The effect of WnT pathway modulators on human iPSC-derived pancreatic beta cell maturation. (external link)
• Berle, Magnus; Ghila, Luiza; Vethe, Heidrun et al. (2018). Novel protein signatures suggest progression to muscular invasiveness in bladder cancer. (external link)
• Cigliola, Valentina; Ghila, Luiza; Thorel, Fabrizio et al. (2018). Pancreatic islet-autonomous insulin and smoothened-mediated signalling modulate identity changes of glucagon+ α-cells. (external link)
• Vethe, Heidrun; Bjørlykke, Yngvild; Ghila, Luiza et al. (2017). Probing the missing mature β-cell proteomic landscape in differentiating patient iPSC-derived cells. (external link)

Academic lecture

• Mathisen, Andreas Frøslev; Legøy, Thomas Aga; Larsen, Ulrik et al. (2023). Islet maturation and ageing is governed by the Hnf1a transcription factor. (external link)

Editorial

• Ghila, Luiza Mihaela; Furuyama, Kenichiro; Grey, Shane T. et al. (2022). Editorial: Beta-Cell Fate: From Gene Circuits to Disease Mechanisms. (external link)

Abstract

• Wang, Chencheng; Abadpour, Shadab; Aizenshtadt, Alexandra et al. (2021). 402.2: High Glucose Concentration Increases KATP Channel Activity but Suppresses Mitochondrial Respiration Ability in Insulin-producing Cells Regenerated From Stem Cells. (external link)

Popular scientific article

• Bhagchandani, Preksha; Chang, Charles; Zhao, Weichen et al. (2021). Islet transplantation tolerance in animals with defined histocompatibility and diabetes. (external link)

Academic literature review

• Cigliola, Valentina; Ghila, Luiza; Chera, Simona et al. (2019). Tissue repair brakes: A common paradigm in the biology of regeneration: Concise review. (external link)

See a complete overview of publications in Cristin.

2021-2024 Mapping predictive cancer signatures in vivo (funded by Norwegian Cancer Society, PI) 

2020-2023 Supportive therapy for diabetes by increasing the stress endurance and regenerative capacity of beta-cells (funded by EEA and Norway Grants funding scheme, RoNo2019, work package leader)

2019-2020 Differentiating insulin-producing cells from induced pluripotent stem cells derived from diabetes patients (funded by Diabetesforbundet, PI)

2016-2019 Characterization of regulatory mechanisms in differentiating MODY-iPS-derived pancreatic cells (postdoctoral project funded by UiB, PI