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 Table of Contents  
Year : 2017  |  Volume : 1  |  Issue : 3  |  Page : 171-178

Spermatogonial Stem Cell Self - renewal and Differentiation

State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433, China

Date of Submission13-Jul-2017
Date of Web Publication29-Jan-2018

Correspondence Address:
Li-Huan Cao
State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200438
Xin-Hua Lin
State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200438
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2096-2924.224213

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Mammalian spermatogenesis is a complicated and precisely controlled process that requires spermatogonial stem cells (SSCs). SSCs maintain the stem cell pool, balance self-renewal–commitment with differentiation, and produce millions of sperm daily. Self-renewal and differentiation are controlled by intrinsic factors within SSCs and extrinsic factors from the “niche.” In this review, we discuss the biology of SSCs and the factors regulating their self-renewal and differentiation.

Keywords: Differentiation; Self-renewal; Spermatogonial Stem Cells

How to cite this article:
Cao LH, Zhang QL, Lin XH. Spermatogonial Stem Cell Self - renewal and Differentiation. Reprod Dev Med 2017;1:171-8

How to cite this URL:
Cao LH, Zhang QL, Lin XH. Spermatogonial Stem Cell Self - renewal and Differentiation. Reprod Dev Med [serial online] 2017 [cited 2020 Jul 7];1:171-8. Available from: http://www.repdevmed.org/text.asp?2017/1/3/171/224213

  Introduction Top

Spermatogenesis is a complex and coordinated process that produces billions of sperm throughout adult male life. Spermatogonial stem cells (SSCs) form the basis of spermatogenesis. Similar to other tissue-specific stem cells, the SSC population is small; it was estimated to be as low as 0.03% of all germ cells in the rodent testis.[1] A delicate balance has to exist between SSC self-renewal–commitment and differentiation. This critical balance is important to maintain the stem cell pool and producing millions of sperm daily. In fact, excessive SSC self-renewal or differentiation hinders spermatogenesis and leads to male infertility.[2] Several SSC markers have been identified over the past two decades, and many of these proteins have important roles in SSC self-renewal and differentiation. The “niche” microenvironment in which stem cells present also provides extrinsic stimuli to regulate SSC self-renewal and differentiation. Here, we summarize the general characteristics of SSCs and the important factors that regulate SSC self-renewal and differentiation.

  Spermatogonial Stem Cell Biological Activities Top

SSCs originate from primordial germ cells (PGCs), at mice embryonic day 13.5. PGCs give rise to gonocytes, which arrest at the G0/G1 stage, thus halting mitosis. However, gonocytes resume proliferation within the 1st postnatal week.[3] In mice, SSCs first appear at 3–4 days postpartum, whereas differentiated spermatogonia first appear at 6 days postpartum.[4],[5] Functional studies have estimated that there are only 2,000–3,000 SSCs per testis, which represents 10% of the pool of Asingle(As) spermatogonia. This indicates that SSCs make up only a fraction of the As spermatogonial pool.[1],[6],[7]

Huckins and Oakberg proposed a model for SSC self-renewal and differentiation in rodents [Figure 1].[8],[9] There are three major types of spermatogonia, namely, Type A, intermediate, and Type B.[8],[9],[10] Type A spermatogonia can be further subdivided into As, Apaired(Apr), Aaligned(Aal), A1, A2, A3, and A4 spermatogonia. As spermatogonia divide to either generate new As spermatogonia or Apr spermatogonia. When As spermatogonia divide into Apr spermatogonia, telophase is incomplete, leaving an open area of cytoplasmic continuity called a cytoplasmic bridge. In the As model, the initiation of spermatogenesis happens when SSCs divide into Apr spermatogonia. Apr spermatogonia can divide further to generate Aal(4–16) spermatogonia, and Apr cells can differentiate into A1 spermatogonia, which undergo mitosis to develop into A2, A3, and A4 spermatogonia. A4 spermatogonia can then transform into intermediate and Type B spermatogonia, resulting in the formation of spermatozoa.[8],[9],[11] Telophase is incomplete in differentiating SSCs and the subsequent divisions in mouse germ cells.[12],[13] Consequentially, transcripts, proteins, and organelles can be exchanged between these syncytial spermatogenic cells.[14]
Figure 1: SSCs undergo self-renewal and differentiation. As: Single spermatogonia; Apr: Paired spermatogonia; Aal: Aligned spermatogonia; A1, A2, A3, A4, types A1–A4 spermatogonia; Int: Intermediate spermatogonia; B: Type B spermatogonia. The number of cells at each specific spermatogonial stage is indicated in parenthesis. SSCs: Spermatogonial stem cells.

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The A0/A1 model is another interesting model, which was proposed by Clermont and Bustos-Obregon.[15] In this model, the A0 spermatogonia, as “reserve” stem cells, are quiescent As, Apr, and Aal spermatogonia, spermatogonial differentiation starts with the In spermatogonia.[15],[16]

Recently, the clonal fragmentation model was also described. Yoshida group found that chains of Apr and Aal spermatogonia were seen to fragment into singles and pairs during the life-imaging experiments occasionally.[5] In this model, a small population of Aal spermatogonia is not committed to differentiation, appearing to recover their stem cell potential by fragmentation.[17],[18],[19] However, a review published recently stated that the clonal fragmentation model is not convincing.[20] It is possible that the fragmentation of larger clones to singles and pairs might due to the photodamage in the life-imaging situation. Yoshida group have not provided direct evidence that the single As spermatogonia that were formed by clonal fragmentation were functional stem cells and did not differentiate into A1 spermatogonia.[20]

  Mouse Spermatogonia Surface Markers Top

The undifferentiated spermatogonia (As, Apr, and Aal) can be easily distinguished from differentiated spermatogonia by their nuclear appearance, undifferentiated spermatogonia are characterized by large nuclei that generally lack heterochromatin.[2],[11],[21] However, undifferentiated spermatogonia can only be subdivided according to their clone size.[22] As spermatogonia are these cells that no other spermatogonia cells are closer than 25 μm to each other, and Apr spermatogonia are these cells that only two spermatogonia of the same nuclear morphology are closer than 25 μm to each other,[8],[11] although there are exceptions to this 25 μm rule.[23] On the differentiation of Aal spermatogonia, Aal spermatogonia transformed into A1 spermatogonia through a nondivision process.[24]

Several SSC surface makers have been previously identified, which have helped in the isolation and identification of SSCs from the testis. Unfortunately, many of these markers are not specific for SSCs; they may also be expressed by undifferentiated spermatogonia or other cell types. Currently, SSC transplantation represents the best approach to study SSCs.[7],[25],[26],[27]

The glycosylphosphatidylinositol-anchored glycoprotein molecule Thy1 (CD90) is an SSC surface marker. Based on FACS analysis, approximately 95% of SSCs are Thy1-positive; among this population of Thy1+ - positive spermatogonia cells, approximately 6% are SSCs based on results from a transplantation study.[28] Thus, Thy1 (CD90) is commonly used in the isolation of SSCs. The glial cell line-derived neurotrophic factor (GDNF) receptor Gfrα-1 is another marker used in the identification and isolation of SSCs.[29],[30],[31],[32] Although there are fewer Gfrα1-positive spermatogonia than Thy1-positive spermatogonia in the testis,[33] Gfrα1 is a good marker for studies that address differentiation and the related signal transduction pathways in vitro. Other SSC surface markers, such as α6-integrin (CD49f),[34] β1-integrin (CD29),[34] CD9,[29],[35] EPCAM,[36] GPR125,[37] CDH1 (E-cadherin),[23] and MCAM,[38] have also been identified for use in characterization and isolation. Finally, c-kit, a member of the receptor tyrosine kinase family, is expressed by differentiated spermatogonia, but not SSCs.[24],[39]

  Spermatogonia Molecular Markers Top

Besides the above-mentioned makers, other molecular markers for SSC or undifferentiated spermatogonia have also been identified. Interestingly, many molecular markers are transcription factors, such as PLZF (also known as zbtb16), T (Brachyury), Bcl6b, Sall4, Sohlh1, Sohlh2, Neurogenin 3 (Ngn3) (Atonal protein homolog 5), and Foxo1. Several molecular markers are RNA binding proteins, such as Lin28a/b, Nanos2, and Nanos3.

Some of these molecular markers exhibit unique expression patterns. There are similar expression patterns between PLZF and E-cadherin; both are expressed in As, Apr and Aal spermatogonia.[18] Ngn3 is mainly expressed in Aal spermatogonia,[18],[40] whereas ID4 (Inhibitor of DNA Binding 4) is a marker of As spermatogonia and essential for SSC functions.[41] Interestingly, not all As spermatogonia in the testis are ID4-positive; only 6,000 out of 35,000 As spermatogonia are ID4-positive. PAX7 is also expressed in a small population of As spermatogonia.[42] There are only about 400–500 Pax7-positive cells per testis. BMI1 is another important molecular marker. There are approximately 5,000 BMI1-positive cells per testis, which is mainly expressed by As spermatogonia.[43] As spermatogonia also express ID4.[44] Several RNA binding proteins, such as Nanos2, Nanos3, and Lin28a/b, are also markers of undifferentiated spermatogonia. The pluripotency factor Lin28 is also mainly expressed by As, Apr and Aal spermatogonia.[45] LIN28A can regulate the division of Aal spermatogonia and partly mediate let-7g expression.[46] The retinoic acid (RA)-responsive gene Stra8A, similar to C-kit, is a widely used marker for differentiated spermatogonia.[47]

We summarize the important molecular markers for spermatogonia in [Table 1].
Table 1: Molecular markers for spermatogonia

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  Spermatogonial Stem Cell Niche Top

The stem cell microenvironment, defined as the stem cell niche, provides extrinsic stimuli to stem cells required for self-renewal and differentiation.[76],[77] In mouse testis,  Sertoli cells More Details contribute greatly to the SSC niche; peritubular myoid cells, Leydig cells, macrophages, and endothelial cells also contribute to the niche.

The niche is rich in growth factors required for self-renewal. For example, GDNF was the first growth factor to be identified; it is important for SSC self-renewal and survival.[33],[78] Heterozygous GDNF knockout mice showed a loss of stem cell reserves, whereas those overexpressing GDNF displayed an accumulation of undifferentiated spermatogonia.[79] GDNF is mainly secreted by Sertoli cells,[80],[81] and its secretion is regulated by FSH.[82] A recent study reported that peritubular myoid cells also secrete GDNF in a manner dependent on testosterone.[83],[84] Fibroblast growth factor 2 (FGF2) is another growth factor necessary for SSC self-renewal, and similar to GDNF, FGF2 is secreted by Sertoli cells as well.[33] On the other hand, colony-stimulating factor 1 (CSF1), which is mainly produced by Leydig cells and a small population of peritubular myoid cells,[85] promotes SSC self-renewal.[86] A recent study has reported that testicular macrophages can secrete CSF1 and that it regulates the fate of SSCs or spermatogonia.[87]

Small blood vessels may also contribute to the SSC niche.[76] Stem cells have been shown to exhibit a preference for blood vessels; specifically, undifferentiated spermatogonial clusters have been found near blood vessels, although differentiated A1 and A2 spermatogonia reside away from blood vessels.[88]

  Signaling Pathways for Spermatogonial Stem Cell Self-Renewal Top

Stem cells are defined by their ability to self-renew [Figure 2]. GDNF was the first growth factor to be identified as important for SSC self-renewal. Heterozygous GDNF knockout mice display depleted SSC reserves and SSC self-renewal defects, whereas mice overexpressing GDNF exhibit abnormal SSC self-renewal.[79] GDNF is mainly secreted by Sertoli cells and peritubular myoid cells [80],[81] whereas GDNF receptors GFRA1 and c-Ret are expressed by undifferentiated spermatogonia.[89],[90] Both receptors are critical for SSC self-renewal and differentiation. Homozygous mice null for GDNF or c-Ret show defects in sperm production.[90]
Figure 2: Signal transduction pathway for SSC self-renewal. FGF2 and GDNF activate common molecules via the Src family kinases, which activate Ras. Ras stimulates the Akt and MEK pathways. Activation of these pathways induces the expression of the transcription factor ETV5, and then ETV5 can up-regulate the expression of transcription factors BCL6B and LXH1. ETV5 also can induce the expression of c-Ret, a component of the GDNF receptor. FOXO family protein, which is a target of the PI3K/AKT pathway in spermatogonia, can also induce the expression of c-Ret. PLZF can induce the expression of Redd1 (an inhibitor of the mTORC1 pathway), and the up-regulation of Redd1 affects the ability of the mTORC1 pathway to suppress the expression of GDNF receptor components. Interestingly, the transcription factor Sall4 antagonizes PLZF function. Cell factor molecules are in a purple font; cell receptor molecules are in a yellow font; and transcription factor molecules are in a red font. SSC: Spermatogonial stem cell; FGF2: Fibroblast growth factor 2; GDNF: Glial cell line-derived neurotrophic factor; mTORC1: Mammalian target of rapamycin complex 1.

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Other studies found that GDNF-dependent signaling through GFRA1/RET activates both PI3K/AKT and Src family kinase (SFK) signaling pathways.[91],[92],[93] GDNF can induce the expression of Etv5, Bcl6b, and Lhx 1 genes via the SFK signaling pathway.[93] In addition, the PI3K/AKT signaling pathway acts on the FOXO family of transcription factors in spermatogonia.[56],[94] Interestingly, spermatogonia null for Etv5 down-regulate C-ret expression.[95] Foxo1 can also influence C-ret expression, and Foxo1 deficiency results in decreased C-ret expression.[56] GDNF can also activate transcription factors CREB1, ATF1, CREM, and c-FOS through the RAS/ERK1/2 pathway.[96]

Besides GDNF, FGF2 also plays critical roles in SSC self-renewal. Although FGF2 cannot maintain SSC renewal alone in vitro, the inclusion of FGF2 into the medium (with GDNF already present) can promote SSC self-renewal.[97],[98],[99] FGF2 can also up-regulate the expression of Bcl6b, Etv5, and Lhx 1 gene through the MEK signaling pathway.[100] Thus, FGF2 can increase sensitivity to the GDNF signal by enhancing the expression of GDNF-regulated genes,[100],[101]

Another important cell factor, CSF1, is also important for SSC renewal. CSF1 is mainly secreted by Leydig cells,[86] and the CSF1 receptor, CSF1R, is highly expressed by undifferentiated spermatogonia. The inclusion of CSF1 into GDNF-supplemented medium enhances SSC self-renewal in vitro.[86] Interestingly, the inclusion of CSF1 (in the absence of GDNF) into the medium does not enhance SSC self-renewal in vitro.[86]

PLZF was the first transcription factor to be identified as necessary for germ stem cell self-renewal in the testis.[48],[49] The lack of the Plzf gene in mice leads to a gradual loss of germ cells in the testis. Transplantation experiments have shown that germ cells from Plzf mutant mice failed to colonize the recipient testis.[48],[49] Another study reported that PLZF regulates SSC self-renewal by inhibiting the mammalian target of rapamycin complex 1 (mTORC1) pathway. The mTORC1 pathway is believed to play key roles in maintaining the balance of SSC self-renewal and differentiation. In addition, activated mTORC1 can down-regulate GDNF receptor expression. PLZF can induce the expression of Redd1, an inhibitor within the mTORC1 signaling pathway.[51] The transcription factor Sall4 directly antagonizes PLZF function.[59]

  Spermatogonial Stem Cell Differentiation Top

Many proteins have been extensively studied for their function in maintaining SSC self-renewal. By contrast, the roles of these proteins in spermatogonial differentiation have not yet been described in detail.

RA signaling is important for spermatogonial differentiation [Figure 3]. In the VAD (Vitamin A deficient) testis, undifferentiated spermatogonia are unable to differentiate into Type A1 spermatogonia.[24] During SSC differentiation, RA decreases ZBTB16/PLZF expression and increases SOHLH1, SOHLH2, KIT, and SALL4 expression in differentiating spermatogonia.[102],[103],[104] SOHLH1/SOHLH2 are critical for spermatogonial differentiation, as a disruption in the function of SOHLH1/SOHLH2 caused abnormal spermatogonial differentiation in mice.[102]
Figure 3: RA and spermatogonial differentiation. RA transcription activates Stra8 and SALL4 and enhances the translational efficiency of Kit, Sohlh1, and Sohlh2 genes. RA: Retinoic acid.

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With regard to the roles of RA receptors in spermatogonial differentiation, it was found that RA receptor gamma (RARγ) is expressed in Aal spermatogonia but not in As or Apl spermatogonia. A disruption in the function of RARγ in adult mice prevents the transition from Aal to A1 spermatogonia.[105] Several studies suggest that the RAR/RXR heterodimer forms the functional complex and functions in spermatogonial differentiation.[104],[105] Recently, it has been reported that RA signaling regulates the expression of replication-dependent core histone genes in spermatogonia.[106]

  Epigenetic Regulation and Spermatogonial Stem Cell Self-Renewal and Differentiation Top

Several studies indicate that SSC and other spermatogonial cells are heterogeneous in their expression of molecular markers.[28],[44],[60],[64],[66],[68] However, shifts in the epigenetic state can exist in different spermatogonial subpopulations.[64],[107],[108]

DNA methylation undergoes dynamic changes throughout the development of mouse PGCs. Studies have shown that the global DNA methylation level is 70% at E6.5, 10% at E13.5 in PGCs,[109],[110] and 50% in E16.5 prospermatogonia.[111],[112] However, there are no changes in DNA methylation between undifferentiated and differentiation-committed spermatogonia. Therefore, histone modifications may be the main factor regulating the balance of SSC self-renewal and differentiation.[113] Compared to undifferentiated PLZF-positive cells, differentiated KIT-positive cells show a different nuclear localization of H3K9me2 and H3K9me3,[107] and the expression of DNMT3A2 and DNMT3B is also up-regulated in differentiated spermatogonia.[107] It was also found that H3K4me3 and H3K27me3 exist at the promoters of development-related genes in both undifferentiated and differentiated spermatogonia,[113] The coincidence of H3K4me3 (correlated with gene activation) with H3K27me3 (correlated with silencing) is termed “bivalency.” The more explicit mechanism of histone modification on SSC's self-renewal and differentiation balance will be a very interesting research topic.

PLZF is a conserved molecular marker of both human and mouse in undifferentiated spermatogonia.[48],[49] However, PLZF can also function as an epigenetic regulator by inducing the silencing of the L1 gene and inhibiting L1 retrotransposition,[114] Several epigenetic factors, such as JMJD1C, JMJD3E, EDD, and SETDB1, are critical for SSC pool maintenance and differentiation.[115],[116],[117],[118] For example, JMJD1C, a histone H3K9me1/2 demethylase,[119] maintains the SSC pool,[116] whereas JMJD3 is an H3K27me2/3 demethylase and functioned in the process of SSC differentiation.[115] EED is a subunit of the polycomb-repressive complex 2 (PRC2) that functions in the di- and tri-methylation of histone H3K27[118] and is indispensable for SSC differentiation. SETDB1, as a histone H3K9me3 methyltransferase, functions in spermatogonial differentiation by regulating Dazl and Sohlh2 promoters.[102],[120],[121]

Small ncRNAs, including miRNAs and piRNAs, are also important for spermatogenesis. Several miRNAs, such as miR-21, miR-17-92, miR-106b-25, miR-34c, miR146, and miR-106a, are responsible for mouse SSC maintenance and differentiation.[122],[123]

  Conclusion and Perspectives Top

Many molecules and signaling pathways have been found to regulate SSC self-renewal and differentiation. However, our understanding of the detailed mechanisms of SSC self-renewal and differentiation is still very limited. During the process of transformation from undifferentiated spermatogonia to differentiated spermatogonia, the nuclear chromatin status shifts significantly, and the expression of various DNA-binding and RNA-binding proteins is precisely regulated. Thus, epigenetic regulation is believed to play important roles in SSC self-renewal and differentiation. At the same time, the SSC niche is essential for SSC self-renewal and differentiation. Further studies will yield new insights into the mechanisms regulating the SSC niche and the epigenetics underlying SSC self-renewal and differentiation.

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Conflicts of interest

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