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Henryk Zulewski is the Head a.i. of the Clinic of Endocrinology and Diabetogy at the University Hospital Basel. The ultimate goal of his research at the Department of Biomedicine is the generation of insulin producing cells from human adult stem cells. The project is based on the discovery of potential stem cells within pancreatic islets in rodents and man that he made during his postdoctoral stay at Massachusetts General Hospital, Harvard Medical School, Boston. These cells can be cultured in vitro and have the potential to acquire a hepatic phenotype in vivo, with production of human albumin if grafted directly into mouse liver. In vitro, the islet-derived nestin-positive cells also display a mesenchymal phenotype with the potential to differentiate into adipocytic and osteocytic phenotype if exposed to appropriate culture conditions. In addition, they can be directed towards a pancreatic endocrine phenotype with production of somatostatin, insulin, and glucagons, but it was not yet possible to detect glucose dependent insulin secretion. We also explored the potential of adipose tissue-derived mesenchymal stem cells (MSC) to acquire a pancreatic endocrine phenotype. Using serum-free medium supplemented with nicotinamide and other factors known to stimulate differentiation of pancreatic stem cells, we found induction of various crucial pancreatic transcription factors (Ipf-1, Isl-1 Ngn-3) as well as islet proteins (insulin, glucagon and somatostatin), but no insulin secretion, indicating a certain immaturity of the differentiated cells. Similar results were obtained with bone marrow derived MSC. We are currently exploring human immortalized MSC for their potential to express developmental pancreatic genes and their ability to adopt a pancreatic endocrine phenotype.
Another major project of our group uses human differentiated MSC as a model to study adipose tissue metabolism as well as inflammatory processes in vitro. The project is embedded in a research group that consists of Beat Müller, Tanja Radimerski, Jean Grisouard, Mirjam Christ-Crain. We have ongoing collaborations with Cleas Wollheim and Benoit Gauthier form Geneva University on differentiation of stem cells into insulin producing cells, and with Jan Henglster from Leibniz Research Center in Dortmund, Germany on the adoption of hepatic phenotype of our islet-derived cells in vivo. We are collaborating with Urs Eriksson from University Hospital Zürich on a project focused on the potential of adult stem cells to attenuate the destructive effects of autoimmune myocarditis and idiopatic pulmonary fibrosis.
Selected original publications related to stem cells
- Zulewski H, Abraham EJ, Gerlach MJ, Daniel PB, Moritz W, Muller B, Vallejo M, Thomas MK. and Habener JF. (2001). Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes. Diabetes 50:521-33.
- von Mach MA, Hengstler JG, Brulport M, Eberhardt M, Schormann W, Herme M, Prawitt D. Zabel B. Grosche J, Reichenbach A, Muller B, Weilemann LS. and Zulewski H. (2004). In vitro cultured islet-derived progenitor cells of human origin express human albumin in severe combined immunodeficiency mouse liver in vivo. Stem Cells 22:1134-41.
- Eberhardt M, Salmon P, von Mach MA, Hengstler JG, Brulport M, Linscheid P, Seboek D, Oberholzer J, Barbero A, Martin I, Muller B, Trono D. and Zulewski H. (2006). Multipotential nestin and Isl-1 positive mesenchymal stem cells isolated from human pancreatic islets. Biochem Biophys Res Commun. 345:1167-76.
- Timper K, Seboek D, Eberhardt M, Linscheid P, Christ-Crain M, Keller U, Muller B. and Zulewski H. (2006). Human adipose tissue-derived mesenchymal stem cells differentiate into insulin, somatostatin, and glucagon expressing cells. Biochem Biophys Res Commun. 341:1135-40.
- Brulport M, Schormann W, Bauer A, Hermes M, Elsner C, Hammersen FJ, Beerheide W, Spitkovsky D, Hartig W, Nussler A, Horn LC, Edelmann J, Pelz-Ackermann O, Petersen J, Kamprad M, von Mach M, Lupp A, Zulewski H. and Hengstler JG. (2007). Fate of extrahepatic human stem and precursor cells after transplantation into mouse livers. Hepatology 46:861-70.
- Kania G, Blyszczuk P, Valaperti A, Dieterle T, Leimenstoll B, Dirnhofer S, Zulewski H. and Eriksson U. (2008). Prominin-1+/CD133+ bone marrow-derived heart-resident cells suppress experimental autoimmune myocarditis. Cardiovasc Res. 80:236-45.
- Germano D, Blyszczuk P, Valaperti A, Kania G, Dirnhofer S, Landmesser U, Luscher TF, Hunziker L, Zulewski H. and Eriksson U. (2009). Prominin-1/CD133+ lung epithelial progenitors protect from bleomycin-induced pulmonary fibrosis. Am J Respir Crit Care Med. 179:939-49.
Review related to stem cells
- Zulewski H. Differentiation of embryonic and adult stem cells into insulin producing cells. (2008). Panminerva Med. 50:73-9.
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