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Human β-cell Precursors Mature Into Functional Insulin-producing Cells in an Immunoisolation Device: Implications for Diabetes Cell Therapies

Lee, Seung-Hee1,2; Hao, Ergeng3; Savinov, Alexei Y.4; Geron, Ifat3; Strongin, Alex Y.4; Itkin-Ansari, Pamela1,2,3,5

doi: 10.1097/TP.0b013e31819c86ea
Basic and Experimental Research

Background. Islet transplantation is limited by the need for chronic immunosuppression and the paucity of donor tissue. As new sources of human β-cells are developed (e.g., stem cell-derived tissue), transplanting them in a durable device could obviate the need for immunosuppression, while also protecting the patient from any risk of tumorigenicity. Here, we studied (1) the survival and function of encapsulated human β-cells and their progenitors and (2) the engraftment of encapsulated murine β-cells in allo- and autoimmune settings.

Methods. Human islets and human fetal pancreatic islet-like cell clusters were encapsulated in polytetrafluorethylene devices (TheraCyte) and transplanted into immunodeficient mice. Graft survival and function was measured by immunohistochemistry, circulating human C-peptide levels, and blood glucose levels. Bioluminescent imaging was used to monitor encapsulated neonatal murine islets.

Results. Encapsulated human islet-like cell clusters survived, replicated, and acquired a level of glucose responsive insulin secretion sufficient to ameliorate hyperglycemia in diabetic mice. Bioluminescent imaging of encapsulated murine neonatal islets revealed a dynamic process of cell death followed by regrowth, resulting in robust long-term allograft survival. Further, in the non-obese diabetic (NOD) mouse model of type I diabetes, encapsulated primary β-cells ameliorated diabetes without stimulating a detectable T-cell response.

Conclusions. We demonstrate for the first time that human β-cells function is compatible with encapsulation in a durable, immunoprotective device. Moreover, our study suggests that encapsulation of β-cells before terminal differentiation will be a successful approach for new cell-based therapies for diabetes, such as those derived from stem cells.

1 Development and Aging Program, Burnham Institute for Medical Research, La Jolla, CA.

2 Sanford Children’s Health Research Center, Burnham Institute for Medical Research, La Jolla, CA.

3 Departments of Pediatrics and Moores Cancer Center, University of California, San Diego La Jolla, CA.

4 Infectious and Inflammatory Diseases Program, Burnham Institute for Medical Research, La Jolla, CA.

This work was supported by grants from JDRF and the J. W. Kieckhefer Foundation.

5 Address correspondence to: Pamela Itkin-Ansari, Ph.D., Department of Pediatrics, University of California San Diego, 9500 Gilman Dr, MC 0816, La Jolla, CA 92093-0816.

E-mail: pitkinan@ucsd.edu

Received 21 October 2008. Revision requested 12 November 2008.

Accepted 12 December 2008.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

© 2009 Lippincott Williams & Wilkins, Inc.