Review Beta-cell replacement and regeneration: Strategies of cell-based therapy for type 1 diabetes mellitus C. Limbert a , G. Pa¨ th a , F. Jakob b , J. Seufert a, * a Division of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital Freiburg, Freiburg, Germany b Musculoskeletal Research Center, Stem Cell Division, Orthopedic Department, University of Wu¨ rzburg, Wu¨ rzburg, Germany Contents 1. Introduction .................................................................................. 390 2. Islet transplantation ........................................................................... 390 2.1. Human pancreatic islet transplantation ....................................................... 390 2.2. Xenotransplantation ...................................................................... 390 3. Islet regeneration.............................................................................. 391 3.1. In vivo regeneration of beta cells ............................................................. 391 3.2. Ex vivo expansion of human pancreatic islets .................................................. 391 3.3. In vitro generation of human insulin producing cells ............................................. 392 3.4. In vitro generation of beta-cell lines .......................................................... 393 3.5. Embryonic stem cells (EC) .................................................................. 393 3.6. Adult stem/progenitor cells ................................................................. 393 3.7. Pancreatic stem/progenitor cells ............................................................. 394 3.8. Extra-pancreatic stem/progenitor cells ........................................................ 394 diabetes research and clinical practice 79 (2008) 389–399 article info Article history: Received 24 March 2007 Accepted 20 June 2007 Published on line 12 September 2007 Keywords: Diabetes type 1 Stem cells Beta cells Regeneration Cell therapy Diabetes mellitus type 1 Cell therapy Stem cells abstract Pancreatic islet transplantation has demonstrated that long-term insulin independence may be achieved in patients suffering from diabetes mellitus type 1. However, because of limited availability of islet tissue, new sources of insulin producing cells that are responsive to glucose are required. Development of pancreatic beta-cell lines from rodent or human origin has progressed slowly in recent years. Current experiments for ex vivo expansion of beta cells and in vitro differentiation of embryonic and adult stem cells into insulin produ- cing beta-cell phenotypes led to promising results. Nevertheless, the cells generated to date lack important characteristics of mature beta cells and generally display reduced insulin secretion and loss of proliferative capacity. Therefore, much better understanding of the mechanisms that regulate expansion and differentiation of stem/progenitor cells is neces- sary. Here, we review recent advances in the identification of potential cellular sources, and the development of strategies to regenerate or fabricate insulin producing and glucose sensing cells that might enable future cell-based therapies of diabetes mellitus type 1. # 2007 Published by Elsevier Ireland Ltd. * Corresponding author at: Schwerpunkt Endokrinologie/Diabetologie, Abteilung Innere Medizin II, Universita¨ tklinikum Freiburg, Hugstetterstrasse 55, 79106 Freiburg, Germany. Tel.: +49 761 270 3634; fax: +49 761 270 3413. E-mail address: jochen.seufert@uniklinik.freiburg.de (J. Seufert). available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/diabres 0168-8227/$ – see front matter # 2007 Published by Elsevier Ireland Ltd. doi:10.1016/j.diabres.2007.06.016