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      Spermatogonial stem cells and spermatogenesis in mice, monkeys and men

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          Abstract

          Continuous spermatogenesis in post-pubertal mammals is dependent on spermatogonial stem cells (SSCs), which balance self-renewing divisions that maintain stem cell pool with differentiating divisions that sustain continuous sperm production. Rodent stem and progenitor spermatogonia are described by their clonal arrangement in the seminiferous epithelium (e.g., A single, A paired or A aligned spermatogonia), molecular markers (e.g., ID4, GFRA1, PLZF, SALL4 and others) and most importantly by their biological potential to produce and maintain spermatogenesis when transplanted into recipient testes. In contrast, stem cells in the testes of higher primates (nonhuman and human) are defined by description of their nuclear morphology and staining with hematoxylin as A dark and A pale spermatogonia. There is limited information about how dark and pale descriptions of nuclear morphology in higher primates correspond with clone size, molecular markers or transplant potential. Do the apparent differences in stem cells and spermatogenic lineage development between rodents and primates represent true biological differences or simply differences in the volume of research and the vocabulary that has developed over the past half century? This review will provide an overview of stem, progenitor and differentiating spermatogonia that support spermatogenesis; identifying parallels between rodents and primates where they exist as well as features unique to higher primates.

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          Most cited references100

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          Essential role of Plzf in maintenance of spermatogonial stem cells.

          Little is known of the molecular mechanisms whereby spermatogonia, mitotic germ cells of the testis, self-renew and differentiate into sperm. Here we show that Zfp145, encoding the transcriptional repressor Plzf, has a crucial role in spermatogenesis. Zfp145 expression was restricted to gonocytes and undifferentiated spermatogonia and was absent in tubules of W/W(v) mutants that lack these cells. Mice lacking Zfp145 underwent a progressive loss of spermatogonia with age, associated with increases in apoptosis and subsequent loss of tubule structure but without overt differentiation defects or loss of the supporting Sertoli cells. Spermatogonial transplantation experiments revealed a depletion of spermatogonial stem cells in the adult. Microarray analysis of isolated spermatogonia from Zfp145-null mice before testis degeneration showed alterations in the expression profile of genes associated with spermatogenesis. These results identify Plzf as a spermatogonia-specific transcription factor in the testis that is required to regulate self-renewal and maintenance of the stem cell pool.
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            Offspring from oocytes derived from in vitro primordial germ cell-like cells in mice.

            Reconstitution of female germ cell development in vitro is a key challenge in reproductive biology and medicine. We show here that female (XX) embryonic stem cells and induced pluripotent stem cells in mice are induced into primordial germ cell-like cells (PGCLCs), which, when aggregated with female gonadal somatic cells as reconstituted ovaries, undergo X-reactivation, imprint erasure, and cyst formation, and exhibit meiotic potential. Upon transplantation under mouse ovarian bursa, PGCLCs in the reconstituted ovaries mature into germinal vesicle-stage oocytes, which then contribute to fertile offspring after in vitro maturation and fertilization. Our culture system serves as a robust foundation for the investigation of key properties of female germ cells, including the acquisition of totipotency, and for the reconstitution of whole female germ cell development in vitro.
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              Plzf is required in adult male germ cells for stem cell self-renewal.

              Adult germline stem cells are capable of self-renewal, tissue regeneration and production of large numbers of differentiated progeny. We show here that the classical mouse mutant luxoid affects adult germline stem cell self-renewal. Young homozygous luxoid mutant mice produce limited numbers of normal spermatozoa and then progressively lose their germ line after birth. Transplantation studies showed that germ cells from mutant mice did not colonize recipient testes, suggesting that the defect is intrinsic to the stem cells. We determined that the luxoid mutant contains a nonsense mutation in the gene encoding Plzf, a transcriptional repressor that regulates the epigenetic state of undifferentiated cells, and showed that Plzf is coexpressed with Oct4 in undifferentiated spermatogonia. This is the first gene shown to be required in germ cells for stem cell self-renewal in mammals.
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                Author and article information

                Journal
                101316957
                35616
                Stem Cell Res
                Stem Cell Res
                Stem cell research
                1873-5061
                1876-7753
                11 June 2018
                21 April 2018
                May 2018
                20 June 2018
                : 29
                : 207-214
                Affiliations
                Molecular Genetics and Developmental Biology Graduate Program, Department of Obstetrics, Gynecology and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, United States
                Author notes
                [* ]Corresponding author. orwigke@ 123456upmc.edu (K.E. Orwig)
                Article
                NIHMS974268
                10.1016/j.scr.2018.04.009
                6010318
                29730571
                f9b7d457-0714-49f1-b499-2fddc37789c5

                This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/BY-NC-ND/4.0/).

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                Categories
                Article

                Molecular medicine
                spermatogonial stem cells,stem cells,adark,apale,spermatogenic lineage development,testis,male fertility

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