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Wnt signaling promotes proliferation and stemness regulation of spermatogonial stem/progenitor cells

Departments of¹ , Biochemistry and Molecular and Cellular Biology² Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3900 Reservoir Road, Northwest, Washington, District of Columbia 20057, USA

Correspondence should be addressed to M Dym; Email: dymm{at}georgetown.edu

A Üren and M Dym contributed equally to this work and are joint corresponding authors

Spermatogonial stem cells (SSCs) self-renew throughout life to produce progenitor cells that are able to differentiate into spermatozoa. However, the mechanisms underlying the cell fate determination between self-renewal and differentiation have not yet been delineated. Culture conditions and growth factors essential for self-renewal and proliferation of mouse SSCs have been investigated, but no information is available related to growth factors that affect fate determination of human spermatogonia. Wnts form a large family of secreted glycoproteins, the members of which are involved in cell proliferation, differentiation, organogenesis, and cell migration. Here, we show that Wnts and their receptors Fzs are expressed in mouse spermatogonia and in the C18-4 SSC line. We demonstrate that WNT3A induces cell proliferation, morphological changes, and cell migration in C18-4 cells. Furthermore, we show that β-catenin is activated during testis development in 21-day-old mice. In addition, our study demonstrates that WNT3A sustained adult human embryonic stem (ES)-like cells derived from human germ cells in an undifferentiated stage, expressing essential human ES cell transcription factors. These results demonstrate for the first time that Wnt/β-catenin pathways, especially WNT3A, may play an important role in the regulation of mouse and human spermatogonia.

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