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Limited Capacity of Human Adult Islets Expanded In Vitro to Redifferentiate Into Insulin-Producing ß-Cells

¹ Department of Pediatrics, USCD Whittier Institute, University of California at San Diego, La Jolla, California
² Institute for Systems Biology, Seattle, Washington
³ Novocell, San Diego, California

Address correspondence and reprint requests to Alberto Hayek, Department of Pediatrics, USCD Whittier Institute, 9894 Genesee Ave., Ste. 225, La Jolla, CA 92037-3495. E-mail: ahayek{at}ucsd.edu

Abbreviations: DKK1, Dickkopf 1; HTB, human tumor bladder; NIH, National Institutes of Health; Pdx, pancreatic duodenal homeobox; WHI, Whittier Institute

Limited organ availability is an obstacle to the widespread use of islet transplantation in type 1 diabetic patients. To address this problem, many studies have explored methods for expanding functional human islets in vitro for diabetes cell therapy. We previously showed that islet cells replicate after monolayer formation under the influence of hepatocyte growth factor and selected extracellular matrices. However, under these conditions, senescence and loss of insulin expression occur after >15 doublings. In contrast, other groups have reported that islet cells expanded in monolayers for months progressed through a reversible epithelial-to-mesenchymal transition, and that on removal of serum from the cultures, islet-like structures producing insulin were formed (1). The aim of the current study was to compare the two methods for islet expansion using immunostaining, real-time quantitative PCR, and microarrays at the following time points: on arrival, after monolayer expansion, and after 1 week in serum-free media. At this time, cell aliquots were grafted into nude mice to study in vivo function. The two methods showed similar results in islet cell expansion. Attempts at cell differentiation after expansion by both methods failed to consistently recover a ß-cell phenotype. Redifferentiation of ß-cells after expansion is still a challenge in need of a solution.

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