Author contributions: S.B.L., D.S., and D.C.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; K.-Y.P., A.H., and J.U.M.: collection and/or assembly of data; E.A.C.: administrative support and collection and/or assembly of data; V.M.F.: data analysis and interpretation and manuscript writing; S.S.T.: conception and design, financial support, provision of study material or patients, data analysis and interpretation, manuscript writing, and final approval of manuscript. S.B.L., D.S., and D.C. contributed equally to this article.
Tissue-Specific Stem Cells
Article first published online: 9 APR 2012
Copyright © 2012 AlphaMed Press
Volume 30, Issue 5, pages 997–1007, May 2012
How to Cite
Lee, S. B., Seo, D., Choi, D., Park, K.-Y., Holczbauer, A., Marquardt, J. U., Conner, E. A., Factor, V. M. and Thorgeirsson, S. S. (2012), Contribution of Hepatic Lineage Stage-Specific Donor Memory to the Differential Potential of Induced Mouse Pluripotent Stem Cells. STEM CELLS, 30: 997–1007. doi: 10.1002/stem.1074
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLSEXPRESS February 29, 2012.
- Issue published online: 9 APR 2012
- Article first published online: 9 APR 2012
- Accepted manuscript online: 29 FEB 2012 11:22AM EST
- Manuscript Accepted: 11 FEB 2012
- Manuscript Revised: 20 JAN 2012
- Manuscript Received: 31 OCT 2011
- Intramural Research Program of the US National Institutes of Health
- National Cancer Institute, Center for Cancer Research
- Induced pluripotent stem cells;
- Donor memory;
- Hepatocyte lineage cells;
- Hepatic differentiation
Recent studies suggested that induced pluripotent stem cells (iPSCs) retain a residual donor cell gene expression, which may impact their capacity to differentiate into cell of origin. Here, we addressed a contribution of a lineage stage-specific donor cell memory in modulating the functional properties of iPSCs. iPSCs were generated from hepatic lineage cells at an early (hepatoblast-derived, HB-iPSCs) and end stage (adult hepatocyte, AH-iPSCs) of hepatocyte differentiation as well as from mouse embryonic fibroblasts (MEFs-iPSCs) using a lentiviral vector encoding four pluripotency-inducing factors Oct4, Sox2, Klf4, and c-Myc. All resulting iPSC lines acquired iPSCs phenotype as judged by the accepted criteria including morphology, expression of pluripotency markers, silencing of transducing factors, capacity of multilineage differentiation in teratoma assay, and normal diploid karyotype. However, HB-iPSCs were more efficient in directed differentiation toward hepatocytic lineage as compared to AH-iPSCs, MEF-iPSCs, or mouse embryonic stem cells (mESCs). Extensive comparative transcriptome analyses of the early passage iPSCs, donor cells, and mESCs revealed that despite global similarities in gene expression patterns between generated iPSCs and mESCs, HB-iPSCs retained a transcriptional memory (seven upregulated and 17 downregulated genes) typical of the original cells. Continuous passaging of HB-iPSCs erased most of these differences including a superior capacity for hepatic redifferentiation. These results suggest that retention of lineage stage-specific donor memory in iPSCs may facilitate differentiation into donor cell type. The identified gene set may help to improve hepatic differentiation for therapeutic applications and contribute to the better understanding of liver development. STEM CELLS 2012;30:997–1007