Can adult human beta cell progenitors be used for beta cell replacement therapy in diabetes patients?
Beta cell replacement therapy (pancreas or islet transplantation) is a treatment option to achieve normoglycemia in patients with type 1 diabetes. However, future implementation for larger groups of patients is hampered by the lack of donor organs. We explore the possibility to use human adult pancreatic progenitor cells as alternative sources for beta-cell therapy. Islet progenitor cells are obtained from human islet-depleted pancreas and a 3-dimensional culture system has been established which allows the outgrowth and expansion of progenitors. With specific differentiation signals we aim to direct islet progenitors into a beta-cell phenotype. Part of this differentiation process is likely to occur In vivo. We test this by transplanting progenitors under the kidney capsule of diabetic mice.
Our research questions are: Can we identify the stem/progenitor cell population in adult human pancreas? Can we isolate and culture these progenitors to create a potential unlimited cell source for beta-cell generation? Can we efficiently direct the cells (in vitro and/or in vivo) to insulin-producing cells. And can we restore normoglycemia in diabetic mice using these progenitors?
GLP-1 and L-cell regulation:
Glucagon-like peptide 1 (GLP-1) is a powerful stimulator of insulin secretion and therefore GLP-1-based approaches are widely used in type 2 diabetes treatment. This hormone is produced by endocrine L-cells in the gut epithelium, which are renewed every 4-5 days. It is still uncertain how the development of L-cells and their number restriction is mediated. If the numbers of GLP-1-secreting cells can be increased, it may offer a possibility to enhance the body’s natural GLP-1 response. We investigate L-cell differentiation at various levels. Our goal is to understand how L-cell numbers are regulated and to find factors controlling the growth of GLP-1-secreting cells.
Improvement of microvascular maintenance:
Diabetes is early on characterized by the development of microvascular disease which essentially reflects a disturbed interaction between endothelial cells and supporting perivascular stromal cells. This disturbed communication eventually can result in retinopathy in the eye, diabetic nephropathy of the kidney and progressive loss of pancreatic islets (containing insulin producing Beta-cells). Important in maintaining the proper vessels is endothelial-/ stromal cell crosstalk which involves secreted factors such as VEGF, PDGF, TGF-β and Angiopoietins I and 2.
At the luminal interface between flowing blood and the endothelial cell surface a mesh of heparan- and chondroitin sulfate proteoglycans, hyaluronan and various incorporated plasma proteins exists (figure 1). This surface layer, usually referred to as the endothelial glycocalyx, is an important determinant of endothelial function by transferring shear forces to the cytoskeleton, by binding growth factors involved in endothelial remodeling and repair (e.g. VEGF and SDF-1), and by providing a barrier against filtration of plasma proteins. Interestingly, a similar proteoglycan network also exist abluminally between endothelial cells and pericytes which is also involved in distributing and concentrating the proper growth factors to the cell surface. Preliminary data demonstrate accelerated degradation of glycocalyx in cultured endothelium exposed to cardiovascular risk factors, smaller glycocalyces at specific arterial sites in mice and a dramatic reduction of systemic glycocalyx volume in humans challenged with acute inflammation, hyperglycemia and type 1 diabetes.
Therefore, we aim to explore the concept that modifications in these surface structures can mimic the microvascular disease that leads to organ failure in diabetes. As models of a highly vascularized organ system susceptible to cardiovascular (diabetic) risk factors, we study the relation of genetic deletion of various individual components within the endothelial glycocalyx in glomerulus (kidney) and islets of Langerhans (pancreas) on morphology (electron microscopy tomography in collaboration with Leiden) and on changes in function (in vivo). To this purpose, multi-photon excitation fluorescence microscopy will be used to determine several basic parameters of renal physiology in real time, including glomerular filtration, permeability properties and blood flow and beta cell exocytosis (a measure of insulin release) after a glucose challenge.
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