Hebrok, Matthias , PhD
Generation of endocrine progenitors via acinar de-differentiation
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Islet Biology
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: January 1, 2010
Project End Date: December 31, 2013
Islet transplantation has demonstrated that exogenous supply of insulin-producing cells is sufficient to restore normal glucose levels in patients suffering from diabetes. However, to make a cell based treatment a reality, we need to increase the supply of insulin-producing ß-cells for transplantation purposes. This is due to the fact that the number of islets that can be isolated from cadaveric donors is far too small compared to the number of patients who could benefit from this procedure.
There are several ways by which one could generate new ß-cells, either through the use of embryonic stem cell or the induction of expansion of mature ß-cells. While both approaches are promising and are being explored, we propose here to test whether we can use acinar cells, a pancreatic cell type that surrounds the islets and produces enzymes for digestion of food, to develop into progenitor cells that then can turn into ß-cells. The idea is based on recent discoveries that have shown that acinar cells can directly turn into cells, however, these experiments were limited in scope as the level of insulin production was low. We propose to first change the acinar cells into cells that express markers of pancreas stem cells and then to induce the ß-cell differentiation program in these progenitor cells. Given the fact that acinar cells make up the majority of the pancreas, changing acinar cells into ß-cells could have significant therapeutic implications by generating a new source of ß-cells for transplantation purposes.
Mentor: Matthias Hebrok, PhD Postdoctoral Fellow: Limor Landsman, PhD
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
The original research proposal submitted approximately a year ago focused on the trans-differentiation of acinar cells into endocrine cells. Since our first submission, we have focused our efforts on a slightly different aspect of endocrine cell differentiation, the role of the mesenchyme during pancreas formation and endocrine cell development. Many studies have demonstrated that the pancreatic mesenchyme is essential for the formation of both the endocrine and exocrine compartments of the organ. However, the exact nature of the factors that guide the development of these compartments, including the factors that control ß-cell differentiation have not been discovered. To address this question, we have performed a gene array study to identify secreted signals enriched in pancreas but not stomach and duodenal mesenchyme or pancreatic epithelium. These factors are currently investigated with the long term goal to understand if they are sufficient to direct differentiation of pancreatic endocrine cells, both during development in vivo and during guided differentiation of human progenitor cells, including embryonic stem cells and induced pluripotent stem cells.
While significant advances have recently been made with regard to guiding human stem cells towards insulin-producing cells, fully functional beta cells have so far not been generated under tissue culture conditions. This is arguably due to the fact that critical molecules, likely supplied by the surrounding mesenchyme during embryonic development, are missing. Our work focuses on the identification of these molecules, the analysis of their function during pancreas development, and the test of their activities during human stem cell differentiation towards functional beta cells. Thus, our research covers the area of generating more beta cells for cell replacement strategies.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Work over the last years has demonstrated impaired beta cell function or complete elimination of beta cells in type 2 and type 1diabetic patients, respectively. Thus, increasing the number of insulin producing cells would help to combat the disease in both type 1 and 2 diabetic patients. Increasing beta cell mass can potentially be accomplished by different means, however, replenishing beta cell mass via transplantation of insulin-producing beta cells is likely one of the most attractive alternatives. Given the shortage of cadaveric islets for transplantation, generating insulin-producing cells from human stem cell populations under tissue culture conditions has emerged as promising alternative. However, for stem cell derived cells to become a viable cell source, the insulin-producing cells need to be fully functional, e.g. measure and respond to physiological changes in blood glucose, secrete the appropriate amount of insulin to restore normoglycemia, and most importantly, to stop insulin secretion once blood sugar levels have reached the normal niveau.
Currently, we cannot generate such a sophisticated cell under cell culture conditions, in part due to the fact that we still do not know all factors that regulate the development of the endogenous beta cell during embryonic development. One source of signals required for formation of functional beta cells is the mesenchyme, a tissue that surrounds the epithelial part of the pancreas during embryogenesis. We have started to identify the mesenchymal factors and to test them under in vivo conditions by manipulating their expression in transgenic animals. Results from these studies will be important as they provide clues and candidates for factors that can be used to optimize existing 'stem cell to beta cell' differentiation protocols in vitro. Thus, by performing these basic science experiments, we anticipate to optimize the generation of a replenishable source of beta cells that can eventually be used for transplantation experiments in human patients.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I have witnessed diabetes and its complications up front through my father who has been living with type 2 diabetes for the last 43 years. While he is suffering from a mild variant of the disease, his constant vigilance about food and sugar intake and the notion that many of his relatives suffered severe long term complications stemming from the disease have encouraged me to pursue a career in basic science related to diabetes research with the goal to find alternatives to exogenous insulin injections. I truly believe that we are about to enter an era in which cell based therapies become reality and I would like to contribute to this development by helping to generate a replenishable source of insulin-producing cells.
The award will play a critical role in our research efforts as it will allow me to support a talented fellow, Dr. Limor Landsman, who is currently spearheading the efforts described above. Limor has made tremendous advances in 'cracking' the code of mesenchymal signals that regulate pancreas and endocrine cell development and this award will ensure that she can continue these studies. In addition, the Mentor based award will provide me with the opportunity to pick another fellow after Limor has left the laboratory to continue this important work.
In what direction do you see the future of diabetes research going?
As briefly mentioned above, I am convinced that we will soon reach a time in which we can combat common diseases, foremost diabetes, with cell-based therapies. I am optimistic that diabetes will be at the forefront of this medical revolution as the target in this disease is a hormone-producing cell. Thus, rather that placing the stem cell derived cell into the context of the endogenous organ, as would be required for spinal cord injuries or brain diseases, insulin-producing cells can be placed at different locations within the human body and still perform the functional requirement to regulated blood sugar levels.
Thus, I strongly believe that diabetes will be one of the first diseases that can be treated with cell-based therapy. Having said this, I also believe that much work remains to be done to ensure that the final cell product is truly fully functional. Unregulated secretion of insulin from stem cell derived cells is potentially fatal and thus all efforts need to be made to ensure that the full complement of signals provided by the embryonic environment during pancreas formation also guide endocrine cell development under cell culture conditions. The task to generate fully functional and safe beta cells for cell transplantation is a challenging but achievable goal for the near time future.
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