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Research Papers:

Spermatogonial stem cells and progenitors are refractory to reprogramming to pluripotency by the transcription factors Oct3/4, c-Myc, Sox2 and Klf4

Sébastien Corbineau _, Bruno Lassalle, Maelle Givelet, Inès Souissi-Sarahoui, Virginie Firlej, Paul Henri Romeo, Isabelle Allemand, Lydia Riou and Pierre Fouchet

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Oncotarget. 2017; 8:10050-10063. https://doi.org/10.18632/oncotarget.14327

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Abstract

Sébastien Corbineau1,2,3,4, Bruno Lassalle1,2,3,4, Maelle Givelet1,2,3,4,7,8,9, Inès Souissi-Sarahoui2,3,4,6, Virginie Firlej1,2,3,4, Paul Henri Romeo1,2,3,4, Isabelle Allemand5, Lydia Riou1,2,3,4, Pierre Fouchet1,2,3,4

1CEA DRF iRCM SCSR, Laboratoire de Recherche sur la réparation et la Transcription dans les cellules Souches, UMR 967, F-92265 Fontenay-aux-Roses, France

2INSERM, UMR967, F-92265 Fontenay-aux-Roses, France

3Université Paris Diderot, Sorbonne Paris Cité, UMR 967, F-92265 Fontenay-aux-Roses, France

4Université Paris Sud, UMR 967, F-92265 Fontenay-aux-Roses, France

5CEA DRF iRCM SCSR, Laboratoire de Gamétogenèse, Apoptose et Génotoxicité, UMR 967, F-92265 Fontenay-aux-Roses, France

6CEA DRF iRCM SCSR, Laboratoire de Radiopathologie, UMR 967, F-92265 Fontenay-aux-Roses, France

7INSERM U1016, Institut Cochin, Paris 75014, France

8CNRS UMR8104, Paris 75014, France

9Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris 75014, France

Correspondence to:

Pierre Fouchet, email: pierre.fouchet@cea.fr

Keywords: stem cell, germinal, reprogramming, pluripotency, testis

Received: May 03, 2016    Accepted: November 30, 2016    Published: December 28, 2016

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.


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