title: Spermatogonial stem cells and progenitors are refractory to reprogramming to pluripotency by the transcription factors Oct3/4, c-Myc, Sox2 and Klf4.
abstract: The male germinal lineage, which is defined as unipotent, produces sperm through spermatogenesis. However, embryonic primordial germ cells and postnatal spermatogonial stem cells (SSCs) can change their fate and convert to pluripotency in culture when they are not controlled by the testicular microenvironment. The mechanisms underlying these reprogramming processes are poorly understood. Testicular germ cell tumors, including teratoma, share some molecular characteristics with pluripotent cells, suggesting that cancer could result from an abnormal differentiation of primordial germ cells or from an abnormal conversion of SCCs to pluripotency in the testis. Here, we investigated whether the somatic reprogramming factors Oct3/4, Sox2, Klf4 and c-Myc (OSKM) could play a role in SSCs reprogramming and induce pluripotency using a doxycycline-inducible transgenic Col1a1-4F2A-OSKM mouse model. We showed that, in contrast to somatic cells, SSCs from adult mice are resistant to this reprogramming strategy, even in combination with small molecules, hypoxia, or p53 deficiency, which were previously described to favour the conversion of somatic cells to pluripotency. This finding suggests that adult SSCs have developed specific mechanisms to repress reprogramming by OSKM factors, contributing to circumvent testicular cancer initiation events.
authors.affiliation: CEA DRF iRCM SCSR, Laboratoire de Recherche sur la réparation et la Transcription dans les cellules Souches, UMR 967, F-92265 Fontenay-aux-Roses, France.|INSERM, UMR967, F-92265 Fontenay-aux-Roses, France.|Université Paris Diderot, Sorbonne Paris Cité, UMR 967, F-92265 Fontenay-aux-Roses, France.|Université Paris Sud, UMR 967, F-92265 Fontenay-aux-Roses, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Corbineau
authors.affiliation: CEA DRF iRCM SCSR, Laboratoire de Recherche sur la réparation et la Transcription dans les cellules Souches, UMR 967, F-92265 Fontenay-aux-Roses, France.|INSERM, UMR967, F-92265 Fontenay-aux-Roses, France.|Université Paris Diderot, Sorbonne Paris Cité, UMR 967, F-92265 Fontenay-aux-Roses, France.|Université Paris Sud, UMR 967, F-92265 Fontenay-aux-Roses, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Lassalle
authors.affiliation: CEA DRF iRCM SCSR, Laboratoire de Recherche sur la réparation et la Transcription dans les cellules Souches, UMR 967, F-92265 Fontenay-aux-Roses, France.|INSERM, UMR967, F-92265 Fontenay-aux-Roses, France.|Université Paris Diderot, Sorbonne Paris Cité, UMR 967, F-92265 Fontenay-aux-Roses, France.|Université Paris Sud, UMR 967, F-92265 Fontenay-aux-Roses, France.|INSERM U1016, Institut Cochin, Paris 75014, France.|CNRS UMR8104, Paris 75014, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris 75014, France.
authors.forename: Maelle
authors.initials: M
authors.lastname: Givelet
authors.affiliation: INSERM, UMR967, F-92265 Fontenay-aux-Roses, France.|Université Paris Diderot, Sorbonne Paris Cité, UMR 967, F-92265 Fontenay-aux-Roses, France.|Université Paris Sud, UMR 967, F-92265 Fontenay-aux-Roses, France.|CEA DRF iRCM SCSR, Laboratoire de Radiopathologie, UMR 967, F-92265 Fontenay-aux-Roses, France.
authors.forename: Inès
authors.initials: I
authors.lastname: Souissi-Sarahoui
authors.affiliation: CEA DRF iRCM SCSR, Laboratoire de Recherche sur la réparation et la Transcription dans les cellules Souches, UMR 967, F-92265 Fontenay-aux-Roses, France.|INSERM, UMR967, F-92265 Fontenay-aux-Roses, France.|Université Paris Diderot, Sorbonne Paris Cité, UMR 967, F-92265 Fontenay-aux-Roses, France.|Université Paris Sud, UMR 967, F-92265 Fontenay-aux-Roses, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Firlej
authors.affiliation: CEA DRF iRCM SCSR, Laboratoire de Recherche sur la réparation et la Transcription dans les cellules Souches, UMR 967, F-92265 Fontenay-aux-Roses, France.|INSERM, UMR967, F-92265 Fontenay-aux-Roses, France.|Université Paris Diderot, Sorbonne Paris Cité, UMR 967, F-92265 Fontenay-aux-Roses, France.|Université Paris Sud, UMR 967, F-92265 Fontenay-aux-Roses, France.
authors.forename: Paul Henri
authors.initials: PH
authors.lastname: Romeo
authors.affiliation: CEA DRF iRCM SCSR, Laboratoire de Gamétogenèse, Apoptose et Génotoxicité, UMR 967, F-92265 Fontenay-aux-Roses, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Allemand
authors.affiliation: CEA DRF iRCM SCSR, Laboratoire de Recherche sur la réparation et la Transcription dans les cellules Souches, UMR 967, F-92265 Fontenay-aux-Roses, France.|INSERM, UMR967, F-92265 Fontenay-aux-Roses, France.|Université Paris Diderot, Sorbonne Paris Cité, UMR 967, F-92265 Fontenay-aux-Roses, France.|Université Paris Sud, UMR 967, F-92265 Fontenay-aux-Roses, France.
authors.forename: Lydia
authors.initials: L
authors.lastname: Riou
authors.affiliation: CEA DRF iRCM SCSR, Laboratoire de Recherche sur la réparation et la Transcription dans les cellules Souches, UMR 967, F-92265 Fontenay-aux-Roses, France.|INSERM, UMR967, F-92265 Fontenay-aux-Roses, France.|Université Paris Diderot, Sorbonne Paris Cité, UMR 967, F-92265 Fontenay-aux-Roses, France.|Université Paris Sud, UMR 967, F-92265 Fontenay-aux-Roses, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fouchet
mesh_terms: D000072956:Adult Germline Stem Cells / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D015687:Cell Hypoxia; D019070:Cell Lineage; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000187:drug effects; D000067470:Cellular Reprogramming Techniques; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D027261:Fusion Regulatory Protein-1 / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000066450:Mouse Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D027261:Fusion Regulatory Protein-1; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C489428:Myc protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D016159:Tumor Suppressor Protein p53
keywords: germinal; pluripotency; reprogramming; stem cell; testis