Human induced pluripotent stem cells (HiPSCs) appear to be highly similar to human embryonic stem cells (HESCs). Using two genetic lineage-tracing systems, we demonstrate the generation of iPSC lines from human pancreatic islet beta cells. These reprogrammed cells acquired markers of pluripotent cells and differentiated into the three embryonic germ layers. However, the beta cell-derived iPSCs (BiPSCs) maintained open chromatin structure at key beta-cell genes, together with a unique DNA methylation signature that distinguishes them from other PSCs. BiPSCs also demonstrated an increased ability to differentiate into insulin-producing cells both in vitro and in vivo, compared with ESCs and isogenic non-beta iPSCs. Our results suggest that the epigenetic memory may predispose BiPSCs to differentiate more readily into insulin producing cells. These findings demonstrate that HiPSC phenotype may be influenced by their cells of origin, and suggest that their skewed differentiation potential may be advantageous for cell replacement therapy.
Bibliographical noteFunding Information:
Human islets were provided through the JDRF award 31-2008-413 (ECIT Islets for Basic Research Program) and the Integrated Islet Distribution Program. We thank Leeat Anker-Kitai, Sarah Knoller, Galina Weingarten, Adva Maimon, and Inbal Caspi for technical assistance. We thank Ran Elkon for assistance with the statistical analysis. This research was partially supported by the Juvenile Diabetes Research Foundation and the Israeli Science Foundation. This work was performed in partial fulfillment of the requirements for a Ph.D. degree of O.B.-N. and H.A.R. O.B.-N. is a Clore fellow. O.B.N., H.A.R., S.E., and N.B. conceived and designed the study, analyzed the data, and wrote the paper. O.B.N. and H.A.R. preformed the experimental work.