Germ Cell Transplantation

ABSTRACT

Transplantation of male germ line stem cells from a fertile donor to the testis of an infertile recipient restores donor-derived spermatogenesis in the recipient testis. The resulting sperm pass the donor genotype to the offspring of the recipient. Germ cell transplantation helped to elucidate the biology of male germ line stem cells and their niche in the testis, develop systems to isolate and culture spermatogonial stem cells, examine defects in spermatogenesis, correct male infertility, and introduce genetic changes into the male germ line. Although most widely studied in rodents, germ cell transplantation has been applied to larger mammals, including primates. Potential clinical applications include restoration of fertility in patients who underwent sterilizing treatments for cancer or targeted correction of genetic defects in testicular somatic cells. Recently, ectopic grafting of testis tissue from diverse donor species, including primates, into a mouse host has opened an additional possibility to study spermatogenesis and to produce fertile sperm from immature donors. Testis xenografts are ideally suitable to study toxicants or drugs with the potential to enhance or suppress male fertility without the necessity of performing experiments in the target species. Therefore, transplantation of germ cells and xenografting of testis tissue represent powerful approaches for the study, preservation, and manipulation of male fertility.

KEYWORDS

Germ cells - testis - transplantation - fertility preservation

REFERENCES

• 1 Russell L D, Ettlin R A, SinhaHikim A P, Clegg E D. Mammalian spermatogenesis. In: Russell LD, Ettlin RA, SinhaHikim AP, Clegg ED Histological and Histopathological Evaluation of the Testis. Clearwater, FL; Cache River Press 1990: 1-40
• 2 Huckins C. Spermatogonial stem cell population in adult rats. I. Their morphology, proliferation and maturation.  Anat Rec. 1971;  169 533-558
• 3 Clermont Y. Kinetics of spermatogenesis in mammals: seminiferous epithelium cycle and spermatogonial renewal.  Physiol Rev. 1972;  52 198-236
• 4 Meistrich M L, van Beek M EAB. Spermatogonial stem cells. In: Desjardins C, Ewing LL Cell and Molecular Biology of the Testis New York; Oxford University Press 1993: 266-295
• 5 Brinster R L, Zimmermann J W. Spermatogenesis following male germ-cell transplantation.  Proc Natl Acad Sci USA. 1994;  91 11298-11302
• 6 Brinster R L, Avarbock M R. Germline transmission of donor haplotype following spermatogonial transplantation.  Proc Natl Acad Sci USA. 1994;  91 11303-11307
• 7 Brinster R L. Germline stem cell transplantation and transgenesis.  Science. 2002;  296 2174-2176
• 8 Jiang F-X, Short R V. Male germ cell transplantation in rats: apparent synchronization of spermatogenesis between host and donor seminiferous epithelia.  Int J Androl. 1995;  18 326-330
• 9 Ogawa T, Dobrinski I, Brinster R L. Recipient preparation is critical for spermatogonial transplantation in the rat.  Tissue Cell. 1999;  31 461-472
• 10 Zhang Z, Renfree M B, Short R V. Successful intra- and interspecific male germ cell transplantation in the rat.  Biol Reprod. 2003;  68 961-967
• 11 Clouthier D E, Avarbock M R, Maika S D, Hammer R E, Brinster R L. Rat spermatogenesis in mouse testis.  Nature. 1996;  381 418-421
• 12 Kanatsu-Shinohara M, Ogonuki N, Inoue K, Ogura A, Toyokuni S, Shinohara T. Restoration of fertility in infertile mice by transplantation of cryopreserved male germline stem cells.  Hum Reprod. 2003;  18 2660-2667
• 13 Avarbock M R, Brinster C J, Brinster R L. Reconstitution of spermatogenesis from frozen spermatogonial stem cells.  Nat Med. 1996;  2 693-696
• 14 Dobrinski I, Avarbock M R, Brinster R L. Transplantation of germ cells from rabbits and dogs into mouse testes.  Biol Reprod. 1999;  61 1331-1339
• 15 Dobrinski I, Avarbock M R, Brinster R L. Germ cell transplantation from large domestic animals into mouse testes.  Mol Reprod Dev. 2000;  57 270-279
• 16 Nagano M, McCarrey J R, Brinster R L. Primate spermatogonial stem cells colonize mouse testes.  Biol Reprod. 2001;  64 1409-1416
• 17 Nagano M, Patrizio P, Brinster R L. Long-term survival of human spermatogonial stem cells in mouse testes.  Fertil Steril. 2002;  78 1225-1233
• 18 Zambrowicz B P, Imamoto A, Fiering S, Herzenberg L A, Kerr W G, Soriano P. Disruption of overlapping transcripts in the ROSA βgeo 26 gene trap strain leads to widespread expression of β-galactosidase in mouse embryos and hematopoietic cells.  Proc Natl Acad Sci USA. 1997;  94 3789-3794
• 19 Ventela S, Ohta H, Parvinen M, Nishimune Y. Development of stages of the cycle in mouse seminiferous epithelium after transplantation of green fluorescent protein-labeled spermatogonial stem cells.  Biol Reprod. 2002;  66 1422-1429
• 20 Dobrinski I, Ogawa T, Avarbock M R, Brinster R L. Computer assisted image analysis to assess colonization of recipient seminiferous tubules by spermatogonial stem cells from transgenic donor mice.  Mol Reprod Dev. 1999;  53 142-148
• 21 Ogawa T, Ohmura M, Yumura Y, Sawada H, Kubota Y. Expansion of murine spermatogonial stem cells through serial transplantation.  Biol Reprod. 2003;  68 316-322
• 22 Kanatsu-Shinohara M, Toyokuni S, Morimoto T, Matsui S, Honjo T, Shinohara T. Functional assessment of self-renewal activity of male germline stem cells following cytotoxic damage and serial transplantation.  Biol Reprod. 2003;  68 1801-1807
• 23 Nagano M. Homing efficiency and proliferation kinetics of male germ line stem cells following transplantation in mice.  Biol Reprod. 2003;  69 701-707
• 24 Creemers L B, Meng X, den Ouden K et al.. Transplantation of germ cells from glial cell line-derived neurotrophic factor-overexpressing mice to host testes depleted of endogenous spermatogenesis by fractionated irradiation.  Biol Reprod. 2002;  66 1579-1584
• 25 Schlatt S, Foppiani L, Rolf C, Weinbauer G F, Nieschlag E. Germ cell transplantation into X-irradiated monkey testes.  Hum Reprod. 2002;  17 55-62
• 26 Bucci L R, Meistrich M L. Effects of busulfan on murine spermatogenesis: cytotoxicity, sterility, sperm abnormalities, and dominant lethal mutations.  Mutat Res. 1987;  176 259-268
• 27 Ogawa T, Arechaga J M, Avarbock M R, Brinster R L. Transplantation of testis germinal cells into mouse seminiferous tubules.  Int J Dev Biol. 1997;  41 111-122
• 28 Vecino P, Uranga J A, Arechaga J. Suppression of spermatogenesis for cell transplantation in adult mice.  Protoplasma. 2001;  217 191-198
• 29 Brinster C J, Ryu B-Y, Avarbock M R, Karagenc L, Brinster R L, Orwig K E. Restoration of fertility by germ cell transplantation requires effective recipient preparation.  Biol Reprod. 2003;  69 412-420
• 30 Ogawa T, Dobrinski I, Avarbock M R, Brinster R L. Leuprolide, a gonadotropin-releasing hormone agonist, enhances colonization after spermatogonial transplantation into mouse testes.  Tissue Cell. 1998;  30 583-588
• 31 Shinohara T, Orwig K E, Avarbock M R, Brinster R L. Remodeling of the postnatal mouse testis is accompanied by dramatic changes in stem cell number and niche accessibility.  Proc Natl Acad Sci USA. 2001;  98 6186-6191
• 32 Honaramooz A, Megee S O, Dobrinski I. Germ cell transplantation in pigs.  Biol Reprod. 2002;  66 21-28
• 33 Honaramooz A, Behboodi E, Megee S O et al.. Fertility and germline transmission of donor haplotype following germ cell transplantation in immuno-competent goats.  Biol Reprod. 2003;  69 1260-1264
• 34 Kangasniemi M, Wilson G, Parchuri N, Huhtaniemi I, Meistrich M L. Rapid protection of rat spermatogenic stem cells against procarbazine by treatment with a gonadotropin-releasing hormone antagonist (Nal-Glu) and an antiandrogen (flutamide).  Endocrinology. 1995;  136 2881-2888
• 35 Dobrinski I, Ogawa T, Avarbock M R, Brinster R L. Effect of the GnRH-agonist leuprolide on colonization of recipient testes by donor spermatogonial stem cells after transplantation in mice.  Tissue Cell. 2001;  33 200-207
• 36 Ohmura M, Ogawa T, Ono M et al.. Increment of murine spermatogonial cell number by gonadotropin-releasing hormone analogue is independent of stem cell factor c-kit signal.  Biol Reprod. 2003;  68 2304-2313
• 37 Tegelenbosch R AJ, de Rooij D G. A quantitative study of spermatogonial multiplication and stem cell renewal in the C3H/101 F₁ hybrid mouse.  Mutat Res. 1993;  290 193-200
• 38 Shinohara T, Avarbock M R, Brinster R L. Functional analysis of spermatogonial stem cells in Steel and cryptorchid infertile mouse models.  Dev Biol. 2000;  220 401-411
• 39 McLean D J, Russell L D, Griswold M D. Biological activity and enrichment of spermatogonial stem cells in vitamin A-deficient and hyperthermia-exposed testes from mice based on colonization following germ cell transplantation.  Biol Reprod. 2002;  66 1374-1379
• 40 Lassalle B, Bastos H, Louis J P et al.. ‘Side population’ cells in adult mouse testis express Bcrp1 gene and are enriched in spermatogonia and germinal stem cells.  Development. 2004;  131 479-487
• 41 Goodell M A, Brose K, Paradis G, Conner A S, Mulligan R C. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo.  J Exp Med. 1996;  183 1797-1806
• 42 Goodell M A, Rosenzweig M, Kim H et al.. Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species.  Nat Med. 1997;  3 1337-1345
• 43 Kubota H, Avarbock M R, Brinster R L. Spermatogonial stem cells share some, but not all, phenotypic and functional characteristics with other stem cells.  Proc Natl Acad Sci USA. 2003;  100 6487-6492
• 44 Hamra F K, Schultz N, Chapman K M et al.. Defining the spermatogonial stem cell.  Dev Biol. 2004;  269 393-410
• 45 Ohta H, Yomogida K, Dohmae K, Nishimune Y. Regulation of proliferation and differentiation in spermatogonial stem cells: the role of c-kit and its ligand SCF.  Development. 2000;  127 2125-2131
• 46 Meng X, Lindahl M, Hyonen M E et al.. Regulation of cell fate decision of undifferentiated spermatogonia by GDNF.  Science. 2000;  287 1489-1493
• 47 Nagano M, Avarbock M R, Leonida E B, Brinster C J, Brinster R L. Culture of mouse spermatogonial stem cells.  Tissue Cell. 1998;  30 389-397
• 48 Nagano M, Ryu B-Y, Brinster C J, Avarbock M R, Brinster R L. Maintenance of mouse male germ line stem cells in vitro.  Biol Reprod. 2003;  68 2207-2214
• 49 Kanatsu-Shinohara M, Ogonuki N, Inoue K et al.. Long-term proliferation in culture and germline transmission of mouse male germline stem cells.  Biol Reprod. 2003;  69 612-616
• 50 van Pelt A MM, Roepers-Gajadien H L, Gademan I S, Creemers L B, de Rooij D G, van Dissel-Emiliani F MF. Establishment of cell lines with rat spermatogonial stem cell characteristics.  Endocrinology. 2002;  143 1845-1850
• 51 Feng L-X, Chen Y, Dettin L et al.. Generation and in vitro differentiation of a spermatogonial cell line.  Science. 2002;  297 392-395
• 52 Ogawa T, Dobrinski I, Avarbock M R, Brinster R L. Transplantation of male germ line stem cells restores fertility in infertile mice.  Nat Med. 2000;  6 29-34
• 53 Franca L R, Ogawa T, Avarbock M R, Brinster R L, Russell L D. Germ cell genotype controls cell cycle during spermatogenesis in the rat.  Biol Reprod. 1998;  59 1371-1377
• 54 Ikawa M, Tergaronkar V, Ogura A, Ogonuki N, Inoue K, Verma I M. Restoration of spermatogenesis by lentiviral gene transfer: offspring from infertile mice.  Proc Natl Acad Sci USA. 2002;  99 7524-7529
• 55 Kanatsu-Shinohara M, Ogura A, Ikegawa M et al.. Adenovirus-mediated gene delivery and in vitro microinsemination produce offspring from infertile male mice.  Proc Natl Acad Sci USA. 2002;  99 1383-1388
• 56 Shinohara T, Orwig K E, Avarbock M R, Brinster R L. Restoration of spermatogenesis in infertile mice by Sertoli cell transplantation.  Biol Reprod. 2003;  68 1064-1071
• 57 Ogawa T, Dobrinski I, Avarbock M R, Brinster R L. Xenogeneic spermatogenesis following transplantation of hamster germ cells to mouse testes.  Biol Reprod. 1999;  60 515-521
• 58 Honaramooz A, Behboodi E, Blash S, Megee S O, Dobrinski I. Germ cell transplantation in goats.  Mol Reprod Dev. 2003;  64 422-428
• 59 Schlatt S, Rosiepen G, Weinbauer G F, Rolf C, Brook P F, Nieschlag E. Germ cell transfer into rat, bovine, monkey and human testes.  Hum Reprod. 1999;  14 144-150
• 60 Izadyar F, den Ouden K, Stout T AE et al.. Autologous and homologous transplantation of bovine spermatogonial stem cells.  Reproduction. 2003;  126 765-774
• 61 Radford J A, Shalet S M, Lieberman B A. Fertility after treatment for cancer.  BMJ. 1999;  319 935-936
• 62 Brook P F, Radford J A, Shalet S M, Joyce A D, Gosden R G. Isolation of germ cells from human testicular tissue for low temperature storage and autotransplantation.  Fertil Steril. 2001;  75 269-274
• 63 Radford J. Restoration of fertility after treatment for cancer.  Horm Res. 2003;  59(suppl 1) 21-23
• 64 Jahnukainen K, Hou M, Petersen C, Setchell B, Soder O. Intratesticular transplantation of testicular cells from leukemic rats causes transmission of leukemia.  Cancer Res. 2001;  61 706-710
• 65 Kanatsu-Shinohara M, Ogonuki N, Inoue K et al.. Allogeneic offspring produced by male germ line stem cell transplantation into infertile mouse testis.  Biol Reprod. 2003;  68 167-173
• 66 Honaramooz A, Snedaker A, Boiani M, Scholer H R, Dobrinski I, Schlatt S. Sperm from neonatal mammalian testes grafted in mice.  Nature. 2002;  418 778-781
• 67 Schlatt S, Kim S S, Gosden R. Spermatogenesis and steroidogenesis in mouse, hamster and monkey testicular tissue after cryopreservation and heterotopic grafting to castrated hosts.  Reproduction. 2002;  124 339-346
• 68 Schlatt S, Honaramooz A, Boiani M, Scholer H R, Dobrinski I. Progeny from sperm obtained after ectopic grafting of neonatal mouse testes.  Biol Reprod. 2003;  68 2331-2335
• 69 Honaramooz A, Li M-W, Penedo M CT, Meyers S A, Dobrinski I. Accelerated maturation of primate testis by xenografting into mice.  Biol Reprod. 2004;  70 1500-1503
• 70 Ohta H, Yomogida K, Tadokoro Y, Tohda A, Dohmae K, Nishimune Y. Defect in germ cells, not supporting cells, is the cause of male infertility in the jsd mutant mouse: proliferation of spermatogonial stem cells without differentiation.  Int J Androl. 2001;  24 15-23
• 71 Boettger-Tong H L, Johnston D S, Russell L D, Griswold M D, Bishop C E. Juvenile spermatogonial depletion (jsd) mutant seminiferous tubules are capable of supporting transplanted spermatogenesis.  Biol Reprod. 2000;  63 1185-1191
• 72 Mahato D, Goulding E H, Korach K S, Eddy E M. Spermatogenic cells do not require estrogen receptor-α for development or function.  Endocrinology. 2000;  141 1273-1276
• 73 Johnston D S, Russell L D, Friel P J, Griswold M D. Murine germ cells do not require functional androgen receptors to complete spermatogenesis following spermatogonial stem cell transplantation.  Endocrinology. 2001;  142 2405-2408
• 74 Wistuba J, Schlatt S, Cantauw C, von Schonfeldt V, Nieschlag E, Behr R. Transplantation of wild-type spermatogonia leads to complete spermatogenesis in testes of cyclic 3′,5′-adenosine monophosphate response element modulator-deficient mice.  Biol Reprod. 2002;  67 1052-1057
• 75 Noguchi J, Toyama Y, Yuasa S, Kikuchi K, Kaneko M. Hereditary defects in both germ cells and the blood-testis barrier system in as-mutant rats: Evidence from spermatogonial transplantation and tracer-permeability analysis.  Biol Reprod. 2002;  67 880-888
• 76 Speed R R, Taggart M, Cooke H J. Spermatogenesis in testes of Dazl null mice after transplantation of wild-type germ cells.  Reproduction. 2003;  126 599-604
• 77 Russell L D, Brinster R L. Ultrastructural observations of spermatogenesis following transplantation of rat testis cells into mouse seminiferous tubules.  J Androl. 1996;  17 615-627
• 78 Izadyar F, Matthijs-Rijsenbilt J J, den Ouden K, Creemers L B, Woelders H, de Rooij D G. Development of a cryopreservation protocol for type A spermatogonia.  J Androl. 2002;  23 537-545
• 79 Reis M M, Tsai M C, Schlegel P N et al.. Xenogeneic transplantation of human spermatogonia.  Zygote. 2000;  8 97-105