Derivation of pluripotent stem cells from nascent undifferentiated teratoma

• Published in: Developmental biology 2019-02, Vol.446 (1), p.43-55
• Main Authors: An, Yuri, Sekinaka, Tamotsu, Tando, Yukiko, Okamura, Daiji, Tanaka, Keiko, Ito-Matsuoka, Yumi, Takehara, Asuka, Yaegashi, Nobuo, Matsui, Yasuhisa
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Cell Differentiation - genetics; Cells, Cultured; Dnd1; Gene Expression Profiling; Gene Expression Regulation, Developmental; Germ cell; Male; Mice; Mice, 129 Strain; Mice, Knockout; Mice, Transgenic; Mouse; Mouse Embryonic Stem Cells - cytology; Mouse Embryonic Stem Cells - metabolism; Nanog Homeobox Protein - genetics; Nanog Homeobox Protein - metabolism; Neoplasm Proteins - deficiency; Neoplasm Proteins - genetics; Octamer Transcription Factor-3 - genetics; Octamer Transcription Factor-3 - metabolism; Pluripotent stem cell; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - metabolism; SOXB1 Transcription Factors - genetics; SOXB1 Transcription Factors - metabolism; Teratoma; Teratoma - genetics; Teratoma - metabolism; Teratoma - pathology; Testis - cytology; Testis - embryology; Testis - metabolism
• ISSN: 0012-1606; 1095-564X
• DOI: 10.1016/j.ydbio.2018.11.020

Teratomas are tumors consisting of components of the three germ layers that differentiate from pluripotent stem cells derived from germ cells. In the normal mouse testis, teratomas rarely form, but a deficiency in Dead-end1 (Dnd1) in mice with a 129/Sv genetic background greatly enhances teratoma formation. Thus, DND1 is crucial for suppression of teratoma development from germ cells. In the Dnd1 mutant testis, nascent teratoma cells emerge at E15.5. To understand the nature of early teratoma cells, we established cell lines in the presence of serum and leukemia inhibitory factor (LIF) from teratoma-forming cells in neonatal Dnd1 mutant testis. These cells, which we designated cultured Dnd1 mutant germ cells (CDGCs), were morphologically similar to embryonic stem cells (ESCs) and could be maintained in the naïve pluripotent condition. In addition, the cells expressed pluripotency genes including Oct4, Nanog, and Sox2; differentiated into cells of the three germ layers in culture; and contributed to chimeric mice. The expression levels of pluripotency genes and global transcriptomes in CDGCs as well as these cells’ adaption to culture conditions for primed pluripotency suggested that their pluripotent status is intermediate between naïve and primed pluripotency. In addition, the teratoma-forming cells in the neonatal testis from which CDGCs were derived also showed gene expression profiles intermediate between naïve and primed pluripotency. The results suggested that germ cells in embryonic testes of Dnd1 mutants acquire the intermediate pluripotent status during the course of conversion into teratoma cells. •Pluripotent cell line CDGCs are established form the nascent teratoma cells.•CDGCs possess intermediate pluripotency between naïve and primed.•The nascent teratoma cells may also harbor the intermediate pluripotency.