Mouse ES and iPS cells can form similar definitive endoderm despite differences in imprinted genes

• Published in: The Journal of clinical investigation 2011-06, Vol.121 (6), p.2313-2325
• Main Authors: Christodoulou, Constantina, Longmire, Tyler A, Shen, Steven S, Bourdon, Alice, Sommer, Cesar A, Gadue, Paul, Spira, Avrum, Gouon-Evans, Valerie, Murphy, George J, Mostoslavsky, Gustavo, Kotton, Darrell N
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Biomedical research; Cell Differentiation - physiology; Cell Line - cytology; Cell Line - metabolism; Cell Lineage; Cell Separation; Chimera; Chromosome Mapping; Clone Cells - cytology; Clone Cells - metabolism; Computer software industry; DNA Methylation; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Endoderm - cytology; Fetal Proteins - biosynthesis; Fetal Proteins - genetics; Gene Expression Regulation, Developmental; Genes; Genes, Reporter; Genomic Imprinting - physiology; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Liver - embryology; Mice; Mice, SCID; Multipotent Stem Cells - cytology; Multipotent Stem Cells - metabolism; Neoplasm Transplantation; Teratoma - pathology; Transcription Factors - biosynthesis; Transcription Factors - genetics
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci43853

The directed differentiation of iPS and ES cells into definitive endoderm (DE) would allow the derivation of otherwise inaccessible progenitors for endodermal tissues. However, a global comparison of the relative equivalency of DE derived from iPS and ES populations has not been performed. Recent reports of molecular differences between iPS and ES cells have raised uncertainty as to whether iPS cells could generate autologous endodermal lineages in vitro. Here, we show that both mouse iPS and parental ES cells exhibited highly similar in vitro capacity to undergo directed differentiation into DE progenitors. With few exceptions, both cell types displayed similar surges in gene expression of specific master transcriptional regulators and global transcriptomes that define the developmental milestones of DE differentiation. Microarray analysis showed considerable overlap between the genetic programs of DE derived from ES/iPS cells in vitro and authentic DE from mouse embryos in vivo. Intriguingly, iPS cells exhibited aberrant silencing of imprinted genes known to participate in endoderm differentiation, yet retained a robust ability to differentiate into DE. Our results show that, despite some molecular differences, iPS cells can be efficiently differentiated into DE precursors, reinforcing their potential for development of cell-based therapies for diseased endoderm-derived tissues.