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Stem Cell Research May 2018Continuous spermatogenesis in post-pubertal mammals is dependent on spermatogonial stem cells (SSCs), which balance self-renewing divisions that maintain stem cell pool... (Review)
Review
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, A or A 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 and A 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.
Topics: Adult Germline Stem Cells; Animals; Cell Differentiation; Cell Lineage; Haplorhini; Humans; Male; Mice; Species Specificity; Spermatogenesis
PubMed: 29730571
DOI: 10.1016/j.scr.2018.04.009 -
Cells Mar 2021Spermatogenesis is a complex and dynamic process which is precisely controlledby genetic and epigenetic factors. With the development of new technologies (e.g.,... (Review)
Review
Spermatogenesis is a complex and dynamic process which is precisely controlledby genetic and epigenetic factors. With the development of new technologies (e.g., single-cell RNA sequencing), increasingly more regulatory genes related to spermatogenesis have been identified. In this review, we address the roles and mechanisms of novel genes in regulating the normal and abnormal spermatogenesis. Specifically, we discussed the functions and signaling pathways of key new genes in mediating the proliferation, differentiation, and apoptosis of rodent and human spermatogonial stem cells (SSCs), as well as in controlling the meiosis of spermatocytes and other germ cells. Additionally, we summarized the gene regulation in the abnormal testicular microenvironment or the niche by Sertoli cells, peritubular myoid cells, and Leydig cells. Finally, we pointed out the future directions for investigating the molecular mechanisms underlying human spermatogenesis. This review could offer novel insights into genetic regulation in the normal and abnormal spermatogenesis, and it provides new molecular targets for gene therapy of male infertility.
Topics: Apoptosis; Cell Differentiation; Gene Expression Regulation; Humans; Infertility, Male; Male; Sertoli Cells; Spermatogenesis
PubMed: 33802813
DOI: 10.3390/cells10030666 -
Cells Mar 2022Spermatogenesis is a prolonged and highly ordered physiological process that produces haploid male germ cells through more than 40 steps and experiences dramatic... (Review)
Review
Spermatogenesis is a prolonged and highly ordered physiological process that produces haploid male germ cells through more than 40 steps and experiences dramatic morphological and cellular transformations. The ubiquitin proteasome system (UPS) plays central roles in the precise control of protein homeostasis to ensure the effectiveness of certain protein groups at a given stage and the inactivation of them after this stage. Many UPS components have been demonstrated to regulate the progression of spermatogenesis at different levels. Especially in recent years, novel testis-specific proteasome isoforms have been identified to be essential and unique for spermatogenesis. In this review, we set out to discuss our current knowledge in functions of diverse USP components in mammalian spermatogenesis through: (1) the composition of proteasome isoforms at each stage of spermatogenesis; (2) the specificity of each proteasome isoform and the associated degradation events; (3) the E3 ubiquitin ligases mediating protein ubiquitination in male germ cells; and (4) the deubiquitinases involved in spermatogenesis and male fertility. Exploring the functions of UPS machineries in spermatogenesis provides a global picture of the proteome dynamics during male germ cell production and shed light on the etiology and pathogenesis of human male infertility.
Topics: Animals; Humans; Male; Mammals; Proteasome Endopeptidase Complex; Proteolysis; Spermatogenesis; Ubiquitin; Ubiquitination
PubMed: 35326509
DOI: 10.3390/cells11061058 -
Animal : An International Journal of... Jun 2018Spermatogenesis is a finely regulated process of germ cell multiplication and differentiation leading to the production of spermatozoa in the seminiferous tubules.... (Review)
Review
Spermatogenesis is a finely regulated process of germ cell multiplication and differentiation leading to the production of spermatozoa in the seminiferous tubules. Spermatogenesis can be divided into three parts: spermatocytogenesis, meiosis and spermiogenesis. During spermatocytogenesis, germ cells engage in a cycle of several mitotic divisions that increases the yield of spermatogenesis and to renew stem cells and produce spermatogonia and primary spermatocytes. Meiosis involves duplication and exchange of genetic material and two cell divisions that reduce the chromosome number and yield four haploid round spermatids. Spermiogenesis involves the differentiation of round spermatids into fully mature spermatozoa released into the lumin of seminiferous tubules. The seminiferous epithelium is composed of several generations of germ cells due to the fact that new generations of sperm cells engage in the spermatogenic process without waiting for the preceding generations to have completed their evolution and to have disappeared as spermatozoa into the lumen of the tubules. In bulls, the duration of the seminiferous epithelium cycle is 13.5 days. The total duration of spermatogenesis is 61 days, that is 4.5 times the duration of the cycle of the seminiferous epithelium. The spermatogenetic wave is used to describe the spatial arrangement of cell associations along the tubules. Several theories have been described to explain the renewal of spermatogonia. Depending on the model, there are five or six spermatogonial mitoses explaining the renewal of stem cells and the proliferation of spermatogonia. Daily sperm production and germ cell degeneration can be quantified from numbers of germ cells in various steps of development throughout spermatogenesis. Bulls have a lower efficiency of spermatogenesis than most species examined, but higher than that of humans.
Topics: Animals; Cattle; Male; Seminiferous Tubules; Spermatocytes; Spermatogenesis; Spermatogonia; Spermatozoa; Testis
PubMed: 29882505
DOI: 10.1017/S1751731118000435 -
Cell Research Sep 2018A systematic interrogation of male germ cells is key to complete understanding of molecular mechanisms governing spermatogenesis and the development of new strategies...
A systematic interrogation of male germ cells is key to complete understanding of molecular mechanisms governing spermatogenesis and the development of new strategies for infertility therapies and male contraception. Here we develop an approach to purify all types of homogeneous spermatogenic cells by combining transgenic labeling and synchronization of the cycle of the seminiferous epithelium, and subsequent single-cell RNA-sequencing. We reveal extensive and previously uncharacterized dynamic processes and molecular signatures in gene expression, as well as specific patterns of alternative splicing, and novel regulators for specific stages of male germ cell development. Our transcriptomics analyses led us to discover discriminative markers for isolating round spermatids at specific stages, and different embryo developmental potentials between early and late stage spermatids, providing evidence that maturation of round spermatids impacts on embryo development. This work provides valuable insights into mammalian spermatogenesis, and a comprehensive resource for future studies towards the complete elucidation of gametogenesis.
Topics: Animals; Male; Mice; Mice, Inbred Strains; Sequence Analysis, RNA; Single-Cell Analysis; Spermatogenesis
PubMed: 30061742
DOI: 10.1038/s41422-018-0074-y -
Human Reproduction Update Feb 2022Autophagy is an intracellular catabolic process of degrading and recycling proteins and organelles to modulate various physiological and pathological events, including... (Review)
Review
BACKGROUND
Autophagy is an intracellular catabolic process of degrading and recycling proteins and organelles to modulate various physiological and pathological events, including cell differentiation and development. Emerging data indicate that autophagy is closely associated with male reproduction, especially the biosynthetic and catabolic processes of sperm. Throughout the fate of sperm, a series of highly specialized cellular events occur, involving pre-testicular, testicular and post-testicular events. Nonetheless, the most fundamental question of whether autophagy plays a protective or harmful role in male reproduction, especially in sperm, remains unclear.
OBJECTIVE AND RATIONALE
We summarize the functional roles of autophagy in the pre-testicular (hypothalamic-pituitary-testis (HPG) axis), testicular (spermatocytogenesis, spermatidogenesis, spermiogenesis, spermiation) and post-testicular (sperm maturation and fertilization) processes according to the timeline of sperm fate. Additionally, critical mechanisms of the action and clinical impacts of autophagy on sperm are identified, laying the foundation for the treatment of male infertility.
SEARCH METHODS
In this narrative review, the PubMed database was used to search peer-reviewed publications for summarizing the functional roles of autophagy in the fate of sperm using the following terms: 'autophagy', 'sperm', 'hypothalamic-pituitary-testis axis', 'spermatogenesis', 'spermatocytogenesis', 'spermatidogenesis', 'spermiogenesis', 'spermiation', 'sperm maturation', 'fertilization', 'capacitation' and 'acrosome' in combination with autophagy-related proteins. We also performed a bibliographic search for the clinical impact of the autophagy process using the keywords of autophagy inhibitors such as 'bafilomycin A1', 'chloroquine', 'hydroxychloroquine', '3-Methyl Adenine (3-MA)', 'lucanthone', 'wortmannin' and autophagy activators such as 'rapamycin', 'perifosine', 'metformin' in combination with 'disease', 'treatment', 'therapy', 'male infertility' and equivalent terms. In addition, reference lists of primary and review articles were reviewed for additional relevant publications. All relevant publications until August 2021 were critically evaluated and discussed on the basis of relevance, quality and timelines.
OUTCOMES
(i) In pre-testicular processes, autophagy-related genes are involved in the regulation of the HPG axis; and (ii) in testicular processes, mTORC1, the main gate to autophagy, is crucial for spermatogonia stem cell (SCCs) proliferation, differentiation, meiotic progression, inactivation of sex chromosomes and spermiogenesis. During spermatidogenesis, autophagy maintains haploid round spermatid chromatoid body homeostasis for differentiation. During spermiogenesis, autophagy participates in acrosome biogenesis, flagella assembly, head shaping and the removal of cytoplasm from elongating spermatid. After spermatogenesis, through PDLIM1, autophagy orchestrates apical ectoplasmic specialization and basal ectoplasmic specialization to handle cytoskeleton assembly, governing spermatid movement and release during spermiation. In post-testicular processes, there is no direct evidence that autophagy participates in the process of capacitation. However, autophagy modulates the acrosome reaction, paternal mitochondria elimination and clearance of membranous organelles during fertilization.
WIDER IMPLICATIONS
Deciphering the roles of autophagy in the entire fate of sperm will provide valuable insights into therapies for diseases, especially male infertility.
Topics: Autophagy; Humans; Infertility, Male; Male; Spermatids; Spermatogenesis; Spermatozoa
PubMed: 34967891
DOI: 10.1093/humupd/dmab043 -
Cell Stem Cell Oct 2018Spermatogenesis generates mature male gametes and is critical for the proper transmission of genetic information between generations. However, the developmental...
Spermatogenesis generates mature male gametes and is critical for the proper transmission of genetic information between generations. However, the developmental landscapes of human spermatogenesis remain unknown. Here, we performed single-cell RNA sequencing (scRNA-seq) analysis for 2,854 testicular cells from donors with normal spermatogenesis and 174 testicular cells from one nonobstructive azoospermia (NOA) donor. A hierarchical model was established, which was characterized by the sequential and stepwise development of three spermatogonia subtypes, seven spermatocyte subtypes, and four spermatid subtypes. Further analysis identified several stage-specific marker genes of human germ cells, such as HMGA1, PIWIL4, TEX29, SCML1, and CCDC112. Moreover, we identified altered gene expression patterns in the testicular somatic cells of one NOA patient via scRNA-seq analysis, paving the way for further diagnosis of male infertility. Our work allows for the reconstruction of transcriptional programs inherent to sequential cell fate transition during human spermatogenesis and has implications for deciphering male-related reproductive disorders.
Topics: Cell Lineage; Cells, Cultured; Computational Biology; Humans; Male; Sequence Analysis, RNA; Single-Cell Analysis; Spermatogenesis; Spermatozoa
PubMed: 30174296
DOI: 10.1016/j.stem.2018.08.007 -
The Journal of Biological Chemistry Dec 2019DNA methylation and histone modifications critically regulate the expression of many genes and repeat regions during spermatogenesis. However, the molecular details of...
DNA methylation and histone modifications critically regulate the expression of many genes and repeat regions during spermatogenesis. However, the molecular details of these processes in male germ cells remain to be addressed. Here, using isolated murine sperm cells, ultra-low-input native ChIP-Seq (ULI-NChIP-Seq), and whole genome bisulfite sequencing (WGBS), we investigated genome-wide DNA methylation patterns and histone 3 Lys-9 trimethylation (H3K9me3) modifications during mouse spermatogenesis. We found that DNA methylation and H3K9me3 have distinct sequence preferences and dynamics in promoters and repeat elements during spermatogenesis. H3K9me3 modifications in histones at gene promoters were highly enriched in round spermatids. H3K9me3 modification on long terminal repeats (LTRs) and long interspersed nuclear elements (LINEs) was involved in silencing active transcription from these regions in conjunction with reestablishment of DNA methylation. Furthermore, H3K9me3 remodeling on the X chromosome was involved in meiotic sex chromosome inactivation and in partial transcriptional reactivation of sex chromosomes in spermatids. Our findings also revealed the DNA methylation patterns and H3K9me3 modification profiles of paternal and maternal germline imprinting control regions (gICRs) during spermatogenesis. Taken together, our results provide a genome-wide map of H3K9me3 modifications during mouse spermatogenesis that may be helpful for understanding male reproductive disorders.
Topics: Animals; DNA Methylation; Epigenomics; Histones; Male; Mice; Protein Processing, Post-Translational; Spermatogenesis; Terminal Repeat Sequences
PubMed: 31662436
DOI: 10.1074/jbc.RA119.010496 -
Cell Stem Cell Feb 2020The human testis undergoes dramatic developmental and structural changes during puberty, including proliferation and maturation of somatic niche cells, and the onset of...
The human testis undergoes dramatic developmental and structural changes during puberty, including proliferation and maturation of somatic niche cells, and the onset of spermatogenesis. To characterize this understudied process, we profiled and analyzed single-cell transcriptomes of ∼10,000 testicular cells from four boys spanning puberty and compared them to those of infants and adults. During puberty, undifferentiated spermatogonia sequentially expand and differentiate prior to the initiation of gametogenesis. Notably, we identify a common pre-pubertal progenitor for Leydig and myoid cells and delineate candidate factors controlling pubertal differentiation. Furthermore, pre-pubertal Sertoli cells exhibit two distinct transcriptional states differing in metabolic profiles before converging to an alternative single mature population during puberty. Roles for testosterone in Sertoli cell maturation, antimicrobial peptide secretion, and spermatogonial differentiation are further highlighted through single-cell analysis of testosterone-suppressed transfemale testes. Taken together, our transcriptional atlas of the developing human testis provides multiple insights into developmental changes and key factors accompanying male puberty.
Topics: Adult; Humans; Infant; Male; Puberty; Sertoli Cells; Spermatogenesis; Spermatogonia; Testis
PubMed: 31928944
DOI: 10.1016/j.stem.2019.12.005 -
International Journal of Molecular... Mar 2020Male infertility affects half of infertile couples and, currently, a relevant percentage of cases of male infertility is considered as idiopathic. Although the male... (Review)
Review
Male infertility affects half of infertile couples and, currently, a relevant percentage of cases of male infertility is considered as idiopathic. Although the male contribution to human fertilization has traditionally been restricted to sperm DNA, current evidence suggest that a relevant number of sperm transcripts and proteins are involved in acrosome reactions, sperm‒oocyte fusion and, once released into the oocyte, embryo growth and development. The aim of this review is to provide updated and comprehensive insight into the molecular biology of spermatogenesis, including evidence on spermatogenetic failure and underlining the role of the sperm-carried molecular factors involved in oocyte fertilization and embryo growth. This represents the first step in the identification of new possible diagnostic and, possibly, therapeutic markers in the field of apparently idiopathic male infertility.
Topics: DNA Fragmentation; Female; Humans; Infertility, Male; Male; Oocytes; Spermatogenesis; Spermatozoa
PubMed: 32138324
DOI: 10.3390/ijms21051728