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TISSUE-SPECIFIC STEM CELLS

Characterization, Cryopreservation, and Ablation of Spermatogonial Stem Cells in Adult Rhesus Macaques

Departments of ^aOb/Gyn & Reproductive Sciences,
^bMolecular Genetics and Biochemistry, and
^cCell Biology and Physiology,
^dCenter for Research in Reproductive Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA;
^ePittsburgh Development Center, Magee-Womens Research Institute & Foundation, Pittsburgh, Pennsylvania, USA;
^fCancer Biology and Genetics Program and Department of Pathology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

Key Words. Busulfan • Chemotherapy • Infertility • Spermatogenesis • Spermatogonial stem cells • Xenotransplantation

Correspondence: Kyle E. Orwig, Ph.D., University of Pittsburgh School of Medicine, Magee-Womens Research Institute & Foundation, 204 Craft Avenue, Pittsburgh, Pennsylvania 15213, USA. Telephone: 412-641-2460; Fax: 412-641-3899; e-mail: korwig{at}pdc.magee.edu

Received on February 25, 2007; accepted for publication on June 8, 2007.

First published online in STEM CELLS EXPRESS  June 21, 2007.


Spermatogonial stem cells (SSCs) are at the foundation of mammalian spermatogenesis. Whereas rare A_single spermatogonia comprise the rodent SSC pool, primate spermatogenesis arises from more abundant A_dark and A_pale spermatogonia, and the identity of the stem cell is subject to debate. The fundamental differences between these models highlight the need to investigate the biology of primate SSCs, which have greater relevance to human physiology. The alkylating chemotherapeutic agent, busulfan, ablates spermatogenesis in rodents and causes infertility in humans. We treated adult rhesus macaques with busulfan to gain insights about its effects on SSCs and spermatogenesis. Busulfan treatment caused acute declines in testis volume and sperm counts, indicating a disruption of spermatogenesis. One year following high-dose busulfan treatment, sperm counts remained undetectable, and testes were depleted of germ cells. Similar to rodents, rhesus spermatogonia expressed markers of germ cells (VASA, DAZL) and stem/progenitor spermatogonia (PLZF and GFR1), and cells expressing these markers were depleted following high-dose busulfan treatment. Furthermore, fresh or cryopreserved germ cells from normal rhesus testes produced colonies of spermatogonia, which persisted as chains on the basement membrane of mouse seminiferous tubules in the primate to nude mouse xenotransplant assay. In contrast, testis cells from animals that received high-dose busulfan produced no colonies. These studies provide basic information about rhesus SSC activity and the impact of busulfan on the stem cell pool. In addition, the germ cell-depleted testis model will enable autologous/homologous transplantation to study stem cell/niche interactions in nonhuman primate testes.

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

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