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Spermatogonial stem cell transplantation into rhesus testes regenerates spermatogenesis producing functional sperm.

ABSTRACT: Spermatogonial stem cells (SSCs) maintain spermatogenesis throughout a man's life and may have application for treating some cases of male infertility, including those caused by chemotherapy before puberty. We performed autologous and allogeneic SSC transplantations into the testes of 18 adult and 5 prepubertal recipient macaques that were rendered infertile with alkylating chemotherapy. After autologous transplant, the donor genotype from lentivirus-marked SSCs was evident in the ejaculated sperm of 9/12 adult and 3/5 prepubertal recipients after they reached maturity. Allogeneic transplant led to donor-recipient chimerism in sperm from 2/6 adult recipients. Ejaculated sperm from one recipient transplanted with allogeneic donor SSCs were injected into 85 rhesus oocytes via intracytoplasmic sperm injection. Eighty-one oocytes were fertilized, producing embryos ranging from four-cell to blastocyst with donor paternal origin confirmed in 7/81 embryos. This demonstration of functional donor spermatogenesis following SSC transplantation in primates is an important milestone for informed clinical translation.

SUBMITTER: Hermann BP

PROVIDER: S-EPMC3580057 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Spermatogonial stem cell transplantation into rhesus testes regenerates spermatogenesis producing functional sperm.

Hermann Brian P BP Sukhwani Meena M Winkler Felicity F Pascarella Julia N JN Peters Karen A KA Sheng Yi Y Valli Hanna H Rodriguez Mario M Ezzelarab Mohamed M Dargo Gina G Peterson Kim K Masterson Keith K Ramsey Cathy C Ward Thea T Lienesch Maura M Volk Angie A Cooper David K DK Thomson Angus W AW Kiss Joseph E JE Penedo Maria Cecilia T MC Schatten Gerald P GP Mitalipov Shoukhrat S Orwig Kyle E KE

Cell stem cell 20121101 5

Spermatogonial stem cells (SSCs) maintain spermatogenesis throughout a man's life and may have application for treating some cases of male infertility, including those caused by chemotherapy before puberty. We performed autologous and allogeneic SSC transplantations into the testes of 18 adult and 5 prepubertal recipient macaques that were rendered infertile with alkylating chemotherapy. After autologous transplant, the donor genotype from lentivirus-marked SSCs was evident in the ejaculated spe ...[more]

PMID: 23122294

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Project description:BackgroundIn male pre-pubertal cancer patients, radiation and chemotherapy impact future fertility by eradication of spermatogonial stem cells (SSCs). In macaques, spermatogenesis could be regenerated by intratesticular transplantation of SSCs, but only a small percentage of spermatozoa produced were of donor origin. Transient hormone suppression with a GnRH antagonist (GnRH-ant) enhanced spermatogenic recovery from transplanted SSCs.ObjectivesTo evaluate donor-derived and endogenous spermatogenic recovery after SSC transplantation into irradiated monkeys and to test whether hormone suppression around the time of transplantation facilitates spermatogenic recovery.Materials and methodsTestes of 15 adult rhesus monkeys were irradiated with 7 Gy and 4 months later transplanted, to one of the testes, with cryopreserved testicular cells containing SSCs from unrelated monkeys. Monkeys were either treated with GnRH-ant for 8 weeks before transplantation, GnRH-ant from 4 weeks before to 4 weeks after transplantation, or with no GnRH-ant. Tissues were harvested 10 months after transplantation.ResultsTwo of the 15 monkeys, a control and a pre-transplantation GnRH-ant-treated, showed substantially higher levels of testicular spermatogenesis and epididymal sperm output in the transplanted side as compared to the untransplanted. Over 84% of epididymal spermatozoa on the transplanted side had the donor genotype and were capable of fertilizing eggs after intracytoplasmic sperm injection forming morulae of the donor paternal origin. Low levels of donor spermatozoa (~1%) were also identified in the epididymis of three additional monkeys. Transplantation also appeared to enhance endogenous spermatogenesis.Discussion and conclusionWe confirmed that SSC transplantation can be used for restoration of fertility in male cancer survivors exposed to irradiation as a therapeutic agent. The success rate of this procedure, however, is low. The success of filling the tubules with the cell suspension, but not the GnRH-ant treatment, was related to the level of colonization by transplanted cells.

Project description:BACKGROUND:Spermatogonial stem cell transplantation (SSCT) could become a fertility restoration tool for childhood cancer survivors. However, since in mice, the colonization efficiency of transplanted spermatogonial stem cells (SSCs) is only 12%, the efficiency of the procedure needs to be improved before clinical implementation is possible. Co-transplantation of mesenchymal stem cells (MSCs) might increase colonization efficiency of SSCs by restoring the SSC niche after gonadotoxic treatment. METHODS:A mouse model for long-term infertility was developed and used to transplant SSCs (SSCT, n?=?10), MSCs (MSCT, n =?10), a combination of SSCs and MSCs (MS-SSCT, n?=?10), or a combination of SSCs and TGFß1-treated MSCs (MSi-SSCT, n?=?10). RESULTS:The best model for transplantation was obtained after intraperitoneal injection of busulfan (40 mg/kg body weight) at 4 weeks followed by CdCl2 (2 mg/kg body weight) at 8 weeks of age and transplantation at 11 weeks of age. Three months after transplantation, spermatogenesis resumed with a significantly better tubular fertility index (TFI) in all transplanted groups compared to non-transplanted controls (P?<?0.001). TFI after MSi-SSCT (83.3?±?19.5%) was significantly higher compared to MS-SSCT (71.5?±?21.7%, P?=?0.036) but did not differ statistically compared to SSCT (78.2?±?12.5%). In contrast, TFI after MSCT (50.2?±?22.5%) was significantly lower compared to SSCT (P?<?0.001). Interestingly, donor-derived TFI was found to be significantly improved after MSi-SSCT (18.8?±?8.0%) compared to SSCT (1.9?±?1.1%; P?<?0.001), MSCT (0.0?±?0.0%; P?<?0.001), and MS-SSCT (3.4?±?1.9%; P?<?0.001). While analyses showed that both native and TGFß1-treated MSCs maintained characteristics of MSCs, the latter showed less migratory characteristics and was not detected in other organs. CONCLUSION:Co-transplanting SSCs and TGFß1-treated MSCs significantly improves the recovery of endogenous SSCs and increases the homing efficiency of transplanted SSCs. This procedure could become an efficient method to treat infertility in a clinical setup, once the safety of the technique has been proven.

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Spermatogonial stem cell transplantation into rhesus testes regenerates spermatogenesis producing functional sperm.

Publications

Spermatogonial stem cell transplantation into rhesus testes regenerates spermatogenesis producing functional sperm.

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