Study of patient-derived induced pluripotent stem cells as a powerful tool for understanding pathogenic mechanisms in diabetes
Belgium (BeMSA) - l'Université libre de Bruxelles ULB, Bruxelles
ULB Center for Diabetes Research Universite Libre de Bruxelles (ULB), Route de Lennik 808, 1070 Brussels (Anderlecht), Belgium
Decio L. Eizirik
Miriam Cnop
English, French
4 weeks
Cities/Months Jan Feb Mar Apr May Jun Jul Augt Sep Oct Nov Dec
No No No No No No Yes Yes No No No No
Type of Research Project
- Basic science
What is the background of the project?

Pancreatic β cell dysfunction and apoptosis are central in the development of diabetes (1). However, the critical pathways involved are poorly understood. Our research interest is to gain further insight into the mechanisms of β cell failure in diabetes and to test novel therapies.
Our group has identified endoplasmic reticulum (ER) stress and mitochondrial dysfunction as cellular responses contributing to β cell failure (2-4). Interestingly, dysregulation in these same pathways and organelles cause loss of functional β cell mass in monogenic forms of diabetes (5). These monogenic forms of diabetes are uncommon (less than 5%), but they provide us with important insight into biological pathways that are crucial to maintain β cell function.
In our induced pluripotent stem cell (iPSC) laboratory, we differentiate diabetic patient-derived stem cells into human pancreatic β cells (6). This powerful tool provides us with a highly relevant disease-in-a-dish model that opens a range of new research avenues and will help us to further understand β cell failure in diabetes.

What is the aim of the project?
In this project, iPSCs from healthy individuals and patients with monogenic forms of diabetes that are due to mutations in genes with a role in ER stress or mitochondrial function will be differentiated in vitro into human pancreatic β cells. Pathogenic mechanisms will be studied and therapeutic targets tested. If successful, our research will also further our understanding of β cell failure in type 2 diabetes, which shares dysregulation of the same biological pathways.
What techniques and methods are used?
The selected candidate will develop skills in molecular and cellular biology including cell culture techniques, immunocytochemistry, gene expression analysis by real-time PCR (polymerase chain reaction) and assessment of β cell function and survival.
What is the role of the student?
- The tasks of the student will be performed on his/her own
- The tasks will be done under supervision
What are the tasks expected to be accomplished by the student?
The selected candidate will assist a postdoctoral fellow working full-time on the project. iPSCs from healthy individuals and patients with monogenic forms of diabetes that are due to mutations in genes with a role in ER stress or mitochondrial function will be differentiated in vitro into human pancreatic β cells. The differentiation efficiency will be monitored at different time points of the process by immunostaining and real-time PCR. If successful, functionality of the β-like cells will be evaluated and compared between the healthy and diabetic patients. Specifically, the capacity of the cells to secrete insulin upon stimulation with glucose and other secretagogues will be examined by ELISA (enzyme-linked immunosorbent assay) and expression of ER stress markers will be evaluated by real-time PCR and immunostaining.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
Yes, literature related to the project will be provided. The student will also participate in weekly laboratory meetings.
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- The student will prepare a scientific report
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?

- Some prior experience in cell culture and cell and molecular biology would be very positive but it is not required
- The candidate will be able to work collaboratively in a team
- High motivation, flexibility as well as curiosity and creative thinking are required
- Excellent skills in spoken and written English

Are there any legal limitations in the student’s involvement
Type of students accepted
This project accepts:
- Medical students
- Graduated students (less than 6 months)
- Students in biomedical fields
- (1) Cnop M; Vidal J; Hull RL; Utzschneider KM; Carr DB; Schraw T; Scherer PE; Boyko EJ; Fujimoto WY; Kahn SE. Progressive loss of beta-cell function leads to worsening glucose tolerance in first-degree relatives of subjects with type 2 diabetes. Diabetes Care. 2007 Mar; 30(3):677-82.
- (2) Kharroubi I; Ladrière L; Cardozo AK; Dogusan Z; Cnop M; Eizirik DL. Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms: role of nuclear factor-kappaB and endoplasmic reticulum stress. Endocrinology. 2004 Nov;145(11):5087-96.
- (3) Cunha DA; Hekerman P; Ladrière L; Bazarra-Castro A; Ortis F; Wakeham MC; Moore F; Rasschaert J; Cardozo AK; Bellomo E; Overbergh L; Mathieu C; Lupi R; Hai T; Herchuelz A; Marchetti P; Rutter GA; Eizirik DL; Cnop M. Initiation and execution of lipotoxic ER stress in pancreatic beta-cells. J Cell Sci. 2008 Jul 15;121(Pt 14):2308-18.
- (4) Marchetti P; Bugliani M; Lupi R; Marselli L; Masini M; Boggi U; Filipponi F; Weir GC; Eizirik DL; Cnop M. The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients. Diabetologia. 2007 Dec;50(12):2486-94.
- (5) Cnop M; Toivonen S; Igoillo-Esteve M; Salpea P. Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic β cells. Mol Metab. 2017; 6:1024-1039.
- (6) Cosentino C; Toivonen S; Diaz Villamil E; Atta M; Ravanat JL; Demine S; Schiavo A; Pachera N; Deglasse JP; Jonas JC; Balboa D; Otonkoski T; Pearson ER; Marchetti P; Eizirik DL; Cnop and Igoillo-Esteve. Pancreatic β cell tRNA hypomethylation and fragmentation link TRMT10A deficiency with diabetes. Nucleic Acids Res 2018; ePub ahead of print September 21.