Granulocyte colony-stimulating factor (G-CSF) promotes spermatogenic regeneration from surviving spermatogonia after high-dose alkylating chemotherapy

Abstract

BackgroundThe lifesaving chemotherapy and radiation treatments that allow patients to survive cancer can also result in a lifetime of side-effects, including male infertility. Infertility in male cancer survivors is thought to primarily result from killing of the spermatogonial stem cells (SSCs) responsible for producing spermatozoa since SSCs turn over slowly and are thereby sensitive to antineoplastic therapies. We previously demonstrated that the cytokine granulocyte colony-stimulating factor (G-CSF) can preserve spermatogenesis after alkylating chemotherapy (busulfan).MethodsMale mice were treated with G-CSF or controls before and/or after sterilizing busulfan treatment and evaluated immediately or 10–19 weeks later for effects on spermatogenesis.ResultsWe demonstrated that the protective effect of G-CSF on spermatogenesis was stable for at least 19 weeks after chemotherapy, nearly twice as long as previously shown. Further, G-CSF treatment enhanced spermatogenic measures 10 weeks after treatment in the absence of a cytotoxic insult, suggesting G-CSF acts as a mitogen in steady-state spermatogenesis. In agreement with this conclusion, G-CSF treatment for 3 days before busulfan treatment exacerbated the loss of spermatogenesis observed with G-CSF alone. Reciprocally, spermatogenic recovery was modestly enhanced in mice treated with G-CSF for 4 days after busulfan. These results suggested that G-CSF promoted spermatogonial proliferation, leading to enhanced spermatogenic regeneration from surviving SSCs. Similarly, there was a significant increase in proportion of PLZF+ undifferentiated spermatogonia that were Ki67+ (proliferating) 1 day after G-CSF treatment.ConclusionsTogether, these results clarify that G-CSF protects spermatogenesis after alkylating chemotherapy by stimulating proliferation of surviving spermatogonia, and indicate it may be useful as a retrospective fertility-restoring treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12958-016-0226-1) contains supplementary material, which is available to authorized users.

Cytokines in Male Fertility and Reproductive Pathologies: Immunoregulation and Beyond

“…Other therapeutic avenues will no doubt be identified, as research dedicated to the preservation of fertility in cancer patients are developed. Encouraging results have been obtained from the administration of granulocyte colony stimulating factor (G-CSF) to male rodents prior to the application of previously sterilizing doses of the chemotherapeutic agent, busulfan ( 167 , 168 ). Important clues to its mode of action in this circumstance may emerge as we better understand how local immune cell functions influence spermatogenesis, as G-CSF is typically administered to support neutrophil function.…”

Melatonin Relieves Busulfan-Induced Spermatogonial Stem Cell Apoptosis of Mouse Testis by Inhibiting Endoplasmic Reticulum Stress

“…However, fertility is often impaired by alkylating agents, such as busulfan, which is a commonly used chemotherapeutic drug [2-4]. Therefore, the quality of life and the preservation of fertility have emerged as significant issues [5].…”

Monophosphoryl lipid A alleviated radiation‐induced testicular injury through TLR4‐dependent exosomes

“…In a study conducted by Antonio Hernandez, G‐CSF and MIP‐2 (CXCL‐2) were found to be important in neutrophils mobilization and recruitment after MPLA treatment, which suggested their potential roles in MPLA response. Moreover, G‐CSF has already been reported to protect spermatogenesis after alkylating chemotherapy . Here, we firstly demonstrated that G‐CSF and MIP‐2 were the two key proteins in exosomes to produce testis radiation protection effect, which may help renew our knowledge of these two molecules in the radiation protection.…”