Identification and Regulation of a Stage-Specific Stem Cell Niche Enriched by Nanog-Positive Spermatogonial Stem Cells in the Mouse Testis§

Authors

  • Sami Ventelä,

    Corresponding author
    1. Department of Physiology,University of Turku, Kiinamyllynkatu, Turku, Finland
    2. Department of Otorhinolaryngology,Turku University Central Hospital, Kiinamyllynkatu, Turku, Finland
    • Department of Otorhinolaryngology, Turku University Hospital, FIN-20521 Turku, Finland
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    • Telephone: +358-50-516-6966; Fax: +358-2-250-2610

  • Juho-Antti Mäkelä,

    1. Department of Physiology,University of Turku, Kiinamyllynkatu, Turku, Finland
    2. Turku Doctoral School of Biomedical Sciences (TuBS), Turku, Finland
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  • Jarmo Kulmala,

    1. Department of Oncology and Radiotherapy,Turku University Central Hospital, Kiinamyllynkatu, Turku, Finland
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  • Jukka Westermarck,

    1. Centre for Biotechnology, University of Turku, Kiinamyllynkatu, Turku, Finland
    2. Department of Pathology,University of Turku, Kiinamyllynkatu, Turku, Finland
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  • Jorma Toppari

    1. Department of Physiology,University of Turku, Kiinamyllynkatu, Turku, Finland
    2. Department of Paediatrics, Turku University Central Hospital, Kiinamyllynkatu, Turku, Finland
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  • Author contributions: S.V. and J.-A.M.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; J.K.: collection and/or assembly of data and data analysis and interpretation; J.W.: conception and design, data analysis and interpretation, and manuscript writing; J.T.: conception and design, financial support, administrative support, data analysis and interpretation, manuscript writing, and final approval of manuscript. S.V. and J.-A.M. contributed equally to this article.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS March 2, 2012.

Abstract

The ability of spermatogonial stem cells to acquire embryonic stem cell (ESC) properties in vitro has recently been of great interest. However, studies focused on the in vivo regulation of testicular stem cells have been hampered because the exact anatomical location of these cells is unknown. Moreover, no specialized stem cell niche substructure has been identified in the mammalian testis thus far. It has also been unclear whether the adult mammalian testis houses pluripotent stem cells or whether pluripotency can be induced only in vitro. Here, we demonstrate, for the first time, the existence of a Nanog-positive spermatogonial stem cell subpopulation located in stage XII of the mouse seminiferous epithelial cycle. The efficiency of the cells from seminiferous tubules with respect to prolonged pluripotent gene expression was correlated directly with stage-specific expression levels of Nanog and Oct4, demonstrating the previously unknown stage-specific regulation of undifferentiated spermatogonia (SPG). Testicular Nanog expression marked a radioresistant spermatogonial subpopulation, supporting its stem cell nature. Furthermore, we demonstrated that p21 acts as an upstream regulator of Nanog in SPG and mouse ESCs, and our results demonstrate that promyelocytic leukemia zinc finger is a specific marker of progenitor SPG. Additionally, we describe a novel method to cultivate Nanog-positive SPG in vitro. This study demonstrates the existence and location of a previously unknown stage-specific spermatogonial stem cell niche and reports the regulation of radioresistant spermatogonial stem cells. STEM CELLS 2012;30:1008–1020

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