Stem cells and diabetes
Diabetes is a common life-long condition and the number of children being diagnosed with type 1 diabetes is increasing. The symptoms can be controlled but there is no cure. There are currently no proven treatments for diabetes using stem cells. However, if beta cells could be made in the lab, it could solve the problem of obtaining the right number and quality of cells to replace the patients’ missing or dysfunctional beta cells through islet transplantation.
Making beta cells from pluripotent stem cells
Pluripotent cells - either embryonic stem cells or induced pluripotent stem cells - can make any cell type in the body and researchers are exploring how to direct these to make fully functional beta cells. Such cells could replace the scarce amount of donor pancreatic islets of Langerhans and in theory offer an unlimited source for transplantation and ultimately also the possibility of a curative treatment for Type 1 Diabetes (T1D). Initially, it was only possible to differentiate human pluripotent stem cells into pancreatic progenitors, which are capable of maturing into all pancreatic cell types, including beta cells. The first clinical trial using human embryonic stem cell-derived pancreatic progenitor cells, which are capable of maturing into insulin-producing beta cells upon engraftment in mice, for the treatment of T1D started in the US in July 2014. The phase 1/2 clinical trial is a test for safety and efficacy. Lately, researchers, including DanStem scientists, have succeeded in producing cells from human pluripotent stem cells that share functional properties with normal beta cells both in the laboratory and in diabetic mice after being transplanted. These beta cells provide more interesting stem cell-derived beta cells to test in patients. It is highly likely that these beta cells soon will be tested in phase 1/2 trials.
Diabetes research at DanStem
The Novo Nordisk Foundation Center for Stem Cell Biology, DanStem at Faculty of Health & Medical Sciences at the University of Copenhagen addresses basic research questions in stem cell and developmental biology. Scientists at the center are also focused on the translation of promising basic research results into new strategies and targets for the development of new therapies for cancer and diabetes.
Basic research questions
Scientists focus on how stem cells differentiate and how a cell’s fate in an organism is determined. Several groups use the development of the pancreas and the specification of insulin-secreting beta cells as a model to answer their research questions.
The group headed by Professor Anne Grapin-Botton focuses on understanding the impact of cellular and organ architecture on the cells’ fate choices in the pancreas and how this information is integrated with cell signalling to control cell differentiation into more specialized cell types.
Professor Palle Serup and his group focus on the signalling events – with emphasis on Notch - that regulate growth and differentiation of pancreatic cell types with special emphasis on the insulin producing beta cell.
Professor Henrik Semb’s basic research aims to define the molecular mechanisms for morphogenetic processes such as tube formation, and how such processes directly and indirectly control specification and commitment of pancreatic progenitors into beta cells.
Diabetes and translational stem cell research - Moving towards patients
The group of Professor Henrik Semb focuses on the translation of the basic research discoveries into new human pluripotent stem cell-based treatment of T1D. Currently the group is testing newly developed scalable differentiation protocols for functional insulin-producing beta cells derived from human pluripotent stem cells. To address the future needs of stem cell-derived beta cells they are developing new strategies for expanding the progenitor cells that normally give rise to beta cells. By newly developed methods for isolating these progenitors the overall strategy for expandable production of beta cells for future cell therapy in T1D include the following steps: 1) isolation of pancreatic progenitors, 2) expansion of the progenitors, 3) methods for freezing/thawing of expanded progenitors, and 4) differentiation of thawed progenitors into functional beta cells. Once these steps have been achieved all protocols will be adapted to cGMP conditions, which will be the basis for obtaining approval for future phase 1/2 trials. The objective is to establish a stem cell-based cell therapy program at University of Copenhagen covering all relevant steps from bench to patient.
The pancreas is located in the abdomen, next to the small intestine and stomach. The cells in the pancreas that make insulin (beta cells) are highlighted in red in this video by Dror Sever and Anne Grapin-Botton.
E14.5 dorsal pancreas
3-D reconstruction of whole-mount imaged Hnf1bCreER;mT/mG E14.5 dorsal pancreas after 24 h of in vivo lineage tracing at clonal density.
Imaris software was used to perform a 3-D reconstruction of dorsal pancreas after masking of background signal in the surrounding mesenchyme. Staining for E-Cadherin (white) enables outlining of the pancreatic epithelium, while membrane GFP (green) represents labelled clones. After 360° spinning, a SOX9 symmetric two-cell clone is shown in high magnification with SOX9 in blue. Next, a NEUROG3 symmetric two-cell clone is displayed in high magnification, showing NEUROG3 in magenta.
The video was made by Hjalte Larsen, The Grapin-Botton lab