de Koning: Diabetes and Beta Cell Regeneration

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The De Koning group studies human pancreatic islets and the generation of insulin producing cells from other cell sources for future treatment of type 1 diabetes.

Replacement therapy with insulin producing beta cells is a feasible option to achieve normal glucose levels in patients with type 1 diabetes. For beta-cell replacement therapy, a donor pancreas must be used, but this can only be performed in a small subgroup of patients due to a lack of donor organs. Therefore, new cell sources for the unlimited generation of insulin producing cells need to be identified.

Endocrine progenitor cell identification and characterisation

We explore the possibility to use human adult pancreatic progenitors and pluripotent stem cells (PSC) as an alternative source for beta-cell therapy.

We previously developed a 3D culture system using human pancreatic exocrine tissue which allows the generation of pancreatic organoids. These pancreatic organoids have a ductal phenotype and a limited capacity to differentiate into insulin-producing cells in vivo using current protocols. The organoids constitute an interesting platform to study factors involved in human pancreatic regeneration.

Research questions related to the use of pancreatic organoids

What is the heterogeneity of adult exocrine tissue (duct and acinar cells) and how does this relate to the heterogeneity of organoid cells?
What are the factors needed to improve differentiation of organoid cells into insulin-producing cells?
Can we identify, isolate and culture subpopulations of pancreatic organoids cells that can generate insulin-producing beta cells (in vitro or in vivo)?

Pluripotent stem cell (PSC) technology opened new scenarios in the field of regenerative medicine because they represent a potential source for cell therapy with their indefinite expansion and capacity to generate all the cell types of a body. However, there are still two main obstacles that must be overcome in order to use them as a source of insulin producing cells: 1) variability in differentiation capacity among different PSC lines; 2) functionality of PSC-derived beta-like cells.

Research questions related to the use of iPSC:

What are the epigenetic barriers and the mechanisms limiting differentiation capacity of some PSC lines?
Can we establish a universal protocol to differentiate PSC into functional beta cells?
How can we improve their functionality in vitro?
Can we cure diabetic mice using PSC-derived beta-like cells?

Pancreatic regeneration and glucose homeostasis

We study the process of diabetes occurrence and progression in mice in order to elucidate the mechanisms and pathways that play a role in the development of the disease. In addition, we study how homeostasis of the organ is maintained in injury and under stress conditions.

Research questions within this project are:

How do pharmacological or physiological interventions in mice change islet cell heterogeneity”?
Can we model the regenerative capacity of the endocrine compartment during these conditions?

Group leader

Eelco de Koning

Eelco de Koning is group leader at the Hubrecht Institute and at the Leiden University Medical Center, and professor of Diabetology at Leiden University. His group studies the Islets of Langerhans containing the insulin producing cells that play a key role in diabetes mellitus. Their long-term goal is to generate insulin producing cells from alternative cell sources for novel cell replacement therapy in diabetes mellitus. To this end, the De Koning group uses culture techniques, intravital microscopy, single-cell transcriptome analysis and animal models to better understand the cell types in the pancreatic islets.

Scientific training and positions

Awards

Other activities

Group members

Eelco de Koning

Principal Investigator

Tim Dielen

Technician

Gitanjali Dharmadhikari

Postdoc

Juri Juksar

PhD Student