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Rev Diabet Stud, 2014, 11(1):115-132 DOI 10.1900/RDS.2014.11.115

Maturation of Stem Cell-Derived Beta-cells Guided by the Expression of Urocortin 3

Talitha van der Meulen, Mark O. Huising

The Salk Institute for Biological Studies, Clayton Laboratories for Peptide Biology, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA
Address correspondence to: Mark O. Huising, e-mail:

Manuscript submitted March 28, 2013; accepted June 26, 2013.

Keywords: type 1 diabetes, insulin, stem cell, pancreatic beta-cell, pancreas development, transplantation, urocortin 3, UCN3, CRF receptor, CRH receptor


Type 1 diabetes (T1D) is a devastating disease precipitated by an autoimmune response directed at the insulin-producing beta-cells of the pancreas for which no cure exists. Stem cell-derived beta-cells show great promise for a cure as they have the potential to supply unlimited numbers of cells that could be derived from a patient's own cells, thus eliminating the need for immunosuppression. Current in vitro protocols for the differentiation of stem cell-derived beta-cells can successfully generate pancreatic endoderm cells. In diabetic rodents, such cells can differentiate further along the beta-cell lineage until they are eventually capable of restoring normoglycemia. While these observations demonstrate that stem cell-derived pancreatic endoderm has the potential to differentiate into mature, glucose-responsive beta-cells, the signals that direct differentiation and maturation from pancreatic endoderm onwards remain poorly understood. In this review, we analyze the sequence of events that culminates in the formation of beta-cells during embryonic development. and summarize how current protocols to generate beta-cells have sought to capitalize on this ontogenic template. We place particular emphasis on the current challenges and opportunities which occur in the later stages of beta-cell differentiation and maturation of transplantable stem cell-derived beta-cells. Another focus is on the question how the use of recently identified maturation markers such as urocortin 3 can be instrumental in guiding these efforts.

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