de Koning: Diabetes and islet neogenesis

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The De Koning group studies development and differentiation of pancreatic cells to improve treatment of type 1 diabetes in the future.

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.

Figure 1. Human pancreatic organoid in 3D culture

Islet progenitor cell identification and characterization

We explore the possibility to use human adult pancreatic progenitor cells as an alternative source for beta-cell therapy. We have obtained islet progenitor cells from human islet-depleted pancreata and have set up a 3-dimensional culture system, which allows the outgrowth and expansion of human pancreatic progenitor cells. Islet progenitors can be directed towards beta cell lineages with specific differentiation signals. In vivo, these progenitors can further differentiate into insulin-producing cells when transplanted under the kidney capsule of diabetic mice.

Research questions within this project are:

Can we identify the stem/progenitor cell in fetal or adult human pancreas?
Can we isolate and culture these progenitors to create a potentially unlimited cell source for beta-cell generation and replacement?
Can we efficiently direct the cells (in vitro/ or in vivo) to insulin-producing cells?
Can we cure diabetic mice using this cell source?

Figure 2. Insulin positive cells (red) in duct cell lining (green) of transplanted organoids

Intravital microscopy after islet cell transplantation

We have developed intravital microscopy techniques to study beta cell fate after transplantation in a dynamic fashion in preclinical animal models. With two-photon intravital imaging through an abdominal imaging window we can visualize the behavior of islet or progenitor cells after transplantation under the kidney capsule at subcellular resolution. Using this technique, we can visualize processes such as organization, vascularization and differentiation of transplanted cells.

Research questions within this project are:

What factors are involved in the differentiation process of transplanted islet cells?
How can we optimize the transplantation site?

Single cell transcriptomics of pancreatic islet and exocrine cells

We are able to sort single cells from the human and mouse adult and embryonic pancreas that we characterize in detail using single cell transcriptome analysis. We perform physiological and pharmaceutical interventions in mice to study the effects of these interventions on single islet cell characteristics. Similar analysis is performed on progenitor cell cultures, both in 2D and 3D culture environments. This way, we can build an atlas of human and mouse islet cells and compare these cells with expansion cultures. In addition, the use of embryonic pancreatic cells will enable us to perform a lineage reconstruction for the cells in the pancreas.

Research questions within this project are:

Can we identify clusters of cells with progenitor characteristics?
What is the extent of islet cell heterogeneity and how can physiological and pharmacological interventions modulate islet cell heterogeneity?
Can we identify specific surface markers that enables us to specifically isolate these cells from larger cell populations?

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