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Hum. Reprod. Advance Access published online on October 8, 2009
Human Reproduction, doi:10.1093/humrep/dep354
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© The Author 2009. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Embryonic stem cell-like cells derived from adult human testis

S.C. Mizrak1,9, J.V. Chikhovskaya1, H. Sadri-Ardekani1,2, S. van Daalen1, C.M. Korver1, S.E. Hovingh1, H.L. Roepers-Gajadien1, A. Raya3,4, K. Fluiter5, Th.M. de Reijke6, J.J.M.C.H. de la Rosette6, A.C. Knegt7, J.C. Belmonte3, F. van der Veen1, D.G. de Rooij1,7,8, S. Repping1 and A.M.M. van Pelt1

1 Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105, AZ Amsterdam, The Netherlands 2 Reproductive Biotechnology Research Center, Avesina Research Institute, Tehran, Iran 3 Center for Regenerative Medicine in Barcelona, Barcelona, Spain 4 Institució Catalana de Recerca i Estudis Avançats (ICREA) and Networking Center of Biomedical Research in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelono, Spain 5 Department of Neurogenetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands 6 Department of Urology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands 7 Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands 8 Department of Endocrinology and Metabolism, Faculty of Science, Utrecht University, Utrecht, The Netherlands

9 Correspondence address. Tel: +31-20-5667403; Fax: +31-20-6977963; E-mail: S.C.Mizrak{at}amc.uva.nl

BACKGROUND: Given the significant drawbacks of using human embryonic stem (hES) cells for regenerative medicine, the search for alternative sources of multipotent cells is ongoing. Studies in mice have shown that multipotent ES-like cells can be derived from neonatal and adult testis. Here we report the derivation of ES-like cells from adult human testis.

METHODS: Testis material was donated for research by four men undergoing bilateral castration as part of prostate cancer treatment. Testicular cells were cultured using StemPro medium. Colonies that appeared sharp edged and compact were collected and subcultured under hES-specific conditions. Molecular characterization of these colonies was performed using RT–PCR and immunohistochemistry. (Epi)genetic stability was tested using bisulphite sequencing and karyotype analysis. Directed differentiation protocols in vitro were performed to investigate the potency of these cells and the cells were injected into immunocompromised mice to investigate their tumorigenicity.

RESULTS: In testicular cell cultures from all four men, sharp-edged and compact colonies appeared between 3 and 8 weeks. Subcultured cells from these colonies showed alkaline phosphatase activity and expressed hES cell-specific genes (Pou5f1, Sox2, Cripto1, Dnmt3b), proteins and carbohydrate antigens (POU5F1, NANOG, SOX2 and TRA-1-60, TRA-1-81, SSEA4). These ES-like cells were able to differentiate in vitro into derivatives of all three germ layers including neural, epithelial, osteogenic, myogenic, adipocyte and pancreatic lineages. The pancreatic beta cells were able to produce insulin in response to glucose and osteogenic-differentiated cells showed deposition of phosphate and calcium, demonstrating their functional capacity. Although we observed small areas with differentiated cell types of human origin, we never observed extensive teratomas upon injection of testis-derived ES-like cells into immunocompromised mice.

CONCLUSIONS: Multipotent cells can be established from adult human testis. Their easy accessibility and ethical acceptability as well as their non-tumorigenic and autogenic nature make these cells an attractive alternative to human ES cells for future stem cell therapies.

Key words: embryonic stem cells/adult human testis/pluripotency/in vitro differentiation

Submitted on October 15, 2008; resubmitted on August 20, 2009; accepted on September 1, 2009.


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H. Sadri-Ardekani, S. C. Mizrak, S. K. M. van Daalen, C. M. Korver, H. L. Roepers-Gajadien, M. Koruji, S. Hovingh, T. M. de Reijke, J. J.M.C.H. de la Rosette, F. van der Veen, et al.
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