Spermatogonial survival after grafting human testicular tissue to immunodeficient mice

Geens, Mieke; Block, Gert De; Goossens, Ellen; Frederickx, Veerle; Steirteghem, André Van; Tournaye, Herman

doi:10.1093/humrep/dei412

Cited by 128 publications

(89 citation statements)

References 34 publications

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“…Xenografting of testis tissues from pig or goat under the skin of immunodeficient mice has been reported to result in complete spermatogenesis (17). Xenografting of human testis tissues has been attempted, but only spermatogonia were obtained (18,19). Xenogeneic spermatogenesis also raises ethical issues and presents the risk of transmission of animal pathogens.…”

Section: Discussionmentioning

confidence: 99%

Isolation of Germ Cells from Leukemia and Lymphoma Cells in a Human In vitro Model: Potential Clinical Application for Restoring Human Fertility after Anticancer Therapy

et al. 2006

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More than 70% of patients survive childhood cancer, but chemotherapy and radiation therapy may cause irreversible impairment of spermatogenesis. To treat infertility secondary to anticancer treatment for childhood cancer, we have developed a procedure to isolate germ cells from leukemic mice by fluorescence-activated cell sorting with two surface markers, and transplantation of isolated germ cells successfully restored fertility without inducing leukemia. In the present study, we analyzed human germ cells and human malignant cells, including five leukemia cell lines and three lymphoma cell lines, by fluorescence-activated cell sorting with antibodies against MHC class I and CD45. Testicular specimens were obtained from a patient who underwent surgery for testicular rupture. In the high forward scatter and low side scatter region, no malignant cells were found in the MHC class I-negative and CD45-negative fraction (the germ cell fraction), with the exception of K562 cells. A total of 39.2% of the germ cells were found in the germ cell fraction. A total of 1.45% of K562 cells were found in the germ cell fraction. Treatment with IFN; induced the expression of MHC class I on K562 cells but not on germ cells and made it possible to isolate germ cells from K562 cells. In conclusion, we isolated human germ cells from malignant cells with two surface markers after treatment with IFN;. Immunophenotyping for each patient will be necessary before isolation and induction of surface marker will be clinically applicable.

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Section: Discussionmentioning

confidence: 99%

Isolation of Germ Cells from Leukemia and Lymphoma Cells in a Human In vitro Model: Potential Clinical Application for Restoring Human Fertility after Anticancer Therapy

et al. 2006

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“…Previous studies have shown that xenografted testis tissue from sexually mature donors is less successful than that from sexually immature donors (Arregui et al 2008). Moreover, complete spermatogenesis has been reported to be absent in the xenografts that contained post-meiotic germ cells at the time of grafting in all species analyzed to date, and most of the mature donor grafts regressed or were found to contain degenerated tubules , Geens et al 2006, Arregui et al 2008, Abrishami et al 2010. Spermatogenesis was arrested at meiosis in grafts from mature horse (Rathi et al 2006), dog (Abrishami et al 2010) and photoregressed hamster testes .…”

Section: Introductionmentioning

confidence: 99%

Regeneration of Leydig cells in ectopically autografted adult mouse testes

et al. 2015

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Ectopic autografting of testis tissue is a promising approach for studying testicular development, male germline preservation and restoration of male fertility. In this study, we examined the fate of various testicular cells in adult mouse testes following ectopic autografting at 1, 2, 4 and 8 weeks post grafting. Histological examination showed no evidence of re-establishment of spermatogenesis in autografts, and progressive degeneration of seminiferous tubules was detected. Expression of germ cell-specific proteins such as POU5F1, DAZL, TNP1, TNP2, PRM1 and PRM2 revealed that, although proliferating and differentiating spermatogenic germ cells such as spermatogonia, spermatocytes and spermatids could survive in autografts until 4 weeks, only terminally differentiated germ cells such as sperm persisted in autografts until 8 weeks. The presence of Sertoli and peritubular myoid cells, as indicated by expression of WT1 and ACTA2 proteins, respectively, was evident in the autografts until 8 weeks. Interestingly, seminal vesicle weight and serum testosterone level were restored in autografted mice by 8 weeks post grafting. The expression of Leydig cell-specific proteins such as CYP11A1, HSD3B2 and LHCGR showed revival of Leydig cell (LC) populations in autografts over time since grafting. Elevated expression of PDGFRA, LIF, DHH and NEFH in autografts indicated de novo regeneration of LC populations. Autografted adult testis can be used as a model for investigating Leydig cell regeneration, steroidogenesis and regulation of the intrinsic factors involved in Leydig cell development. The success of this rodent model can have therapeutic applications for adult human males undergoing sterilizing cancer therapy.

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“…Xenografting of immature testis tissue from several species, including the rhesus macaque, into a nude mouse host results in full spermatogenesis within the grafted tissue (Honaramooz et al, 2004;Rodriguez-Sosa and Dobrinski, 2009). Previous reports of human testis xenografts show limited survival when post-natal tissue is grafted (Geens et al, 2006;Schlatt et al, 2006) and studies of fetal testis xenografts have been limited to descriptive reports of small numbers of second-trimester grafts Skakkebaek et al, 1974;Yu et al, 2006). Therefore, the aim of the present study was to investigate the suitability of human fetal testis xenografting as a technique to recapitulate normal fetal testis development, including germ cell differentiation.…”

Section: Introductionmentioning

confidence: 99%

Xenografting of Human Fetal Testis Tissue: A New Approach to Study Fetal Testis Development and Germ Cell Differentiation

Mitchell

Saunders

Childs

et al. 2011

Obstetrical &Amp; Gynecological Survey

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background: Abnormal fetal testis development can result in disorders of sex development (DSDs) and predispose to later testicular dysgenesis syndrome (TDS) disorders such as testicular germ cell tumours. Studies of human fetal testis development are hampered by the lack of appropriate model, and intervention systems. We hypothesized that human fetal testis xenografts can recapitulate normal development.methods: Human fetal testes (at 9 weeks, n ¼ 4 and 14 -18 weeks gestation, n ¼ 6) were xenografted into male nude mice for 6 weeks, with or without hCG treatment of the host, and evaluated for normal cellular development and function using immunohistochemistry, triple immunofluorescence and testosterone assay. The differentiation and proliferation status of germ cells within xenografts was quantified and compared with age-matched controls.results: Xenografts showed .75% survival with normal morphology. In the first-trimester xenografts seminiferous cord formation was initiated and in first-and second-trimester grafts normal functional development of Sertoli, Leydig and peritubular myoid cells was demonstrated using cell-specific protein markers. Grafts produced testosterone when hosts were treated with hCG (P ¼ 0.004 versus control). Proliferation of germ cells and differentiation from gonocytes (OCT4 + ) into pre-spermatogonia (VASA + ) occurred in grafts and quantification showed this progressed comparably with age-matched ungrafted controls.conclusions: Human fetal testis tissue xenografts demonstrate normal structure, function and development after xenografting, including normal germ cell differentiation. This provides an in vivo system to study normal human fetal testis development and its susceptibility to disruption by exogenous factors (e.g. environmental chemicals). This should provide mechanistic insight into the fetal origins of DSDs and TDS disorders.

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Spermatogonial survival after grafting human testicular tissue to immunodeficient mice

Cited by 128 publications

References 34 publications

Isolation of Germ Cells from Leukemia and Lymphoma Cells in a Human In vitro Model: Potential Clinical Application for Restoring Human Fertility after Anticancer Therapy

Isolation of Germ Cells from Leukemia and Lymphoma Cells in a Human In vitro Model: Potential Clinical Application for Restoring Human Fertility after Anticancer Therapy

Regeneration of Leydig cells in ectopically autografted adult mouse testes

Xenografting of Human Fetal Testis Tissue: A New Approach to Study Fetal Testis Development and Germ Cell Differentiation

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