TSPAN8 Expression Distinguishes Spermatogonial Stem Cells in the Prepubertal Mouse Testis

Mutoji, Kazadi Nadine; Singh, Anukriti; Nguyen, Thu Anh; Gildersleeve, Heidi; Kaucher, Amy V.; Oatley, Melissa J.; Velte, Ellen K.; Geyer, Christopher B.; Cheng, Keren; McCarrey, John R.; Hermann, Brian P.

doi:10.1095/biolreprod.116.144220

Cited by 35 publications

(43 citation statements)

References 75 publications

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“…Activation of this pathway renders target cells responsive to inductive cytokine signaling (Tsuchida and Friedman, 2017), suggesting that the transition from quiescent SSCs to proliferative differentiating spermatogonia may involve responsiveness to cytokines. Transcripts encoding a master, growth-suppressing transcriptional regulator of this pathway, KLF6 (Ghiassi- Nejad et al, 2013), were significantly elevated in putative SSCs from all of our adult human and mouse spermatogonial datasets (Figures S3L-S3O) and in batch RNA sequencing (RNA-seq) results from SSC-enriched TSPAN8 high spermatogonia (Mutoji et al, 2016) and SSC-enriched ID4-EGFP bright spermatogonia (Helsel et al, 2017) from the immature mouse testis.…”

Section: Resultsmentioning

confidence: 96%

The Mammalian Spermatogenesis Single-Cell Transcriptome, from Spermatogonial Stem Cells to Spermatids

et al. 2018

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SUMMARY Spermatogenesis is a complex and dynamic cellular differentiation process critical to male reproduction and sustained by spermatogonial stem cells (SSCs). Although patterns of gene expression have been described for aggregates of certain spermato- genic cell types, the full continuum of gene expression patterns underlying ongoing spermatogenesis in steady state was previously unclear. Here, we catalog single-cell transcriptomes for >62,000 individual spermatogenic cells from immature (postnatal day 6) and adult male mice and adult men. This allowed us to resolve SSC and progenitor spermatogonia, elucidate the full range of gene expression changes during male meiosis and spermiogenesis, and derive unique gene expression signatures for multiple mouse and human spermatogenic cell types and/or subtypes. These transcriptome datasets provide an information-rich resource for studies of SSCs, male meiosis, testicular cancer, male infertility, or contraceptive development, as well as a gene expression roadmap to be emulated in efforts to achieve spermatogenesis in vitro.

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Section: Resultsmentioning

confidence: 96%

The Mammalian Spermatogenesis Single-Cell Transcriptome, from Spermatogonial Stem Cells to Spermatids

et al. 2018

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“…Using these tools, a recent study profiled single ID4-EGFP + spermatogonia from P6 mice to identify bimodal expression of a group of genes known to regulate spermatogonial functions, and identified clusters of cells expressing different levels of select cell surface markers including TSPAN8 (Hermann et al, 2015). In a follow-up study, the population of ID4-EGFP + spermatogonia expressing a high level of TSPAN8 (TSPAN8-Hi) was found to have potent SSC activity by transplantation analyses, whereas the ID4-EGFP + population expressing low levels of TSPAN8 (TSPAN8-Lo) possessed significantly less stem cell capacity (Mutoji et al, 2016). Transcriptome profiling of the ID4-EGFP + / TSPAN8-Hi and ID4-EGFP + /TSPAN8-Lo populations by RNAseq uncovered distinct gene expression signatures (Mutoji et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…In a follow-up study, the population of ID4-EGFP + spermatogonia expressing a high level of TSPAN8 (TSPAN8-Hi) was found to have potent SSC activity by transplantation analyses, whereas the ID4-EGFP + population expressing low levels of TSPAN8 (TSPAN8-Lo) possessed significantly less stem cell capacity (Mutoji et al, 2016). Transcriptome profiling of the ID4-EGFP + / TSPAN8-Hi and ID4-EGFP + /TSPAN8-Lo populations by RNAseq uncovered distinct gene expression signatures (Mutoji et al, 2016). Included in those profiles was significant upregulation of previously defined core SSC maintenance genes (Id4, Bcl6b, Etv5, Lhx1, Nanos2 and T ) and downregulation of known progenitorpromoting genes (Neurog3, Sohlh1 and Kit) in the TSPAN8-Hi population; a profile that is identical to the ID4-EGFP Bright population measured in the current study.…”

Section: Discussionmentioning

confidence: 99%

“…Comparison of the datasets is a solid approach for gaining insight into what might be the core molecular program that defines an SSC. As a first step, we compared the profiles of differentially expressed genes from three different studies: upregulated genes in ID4-EGFP + /TSPAN8-Hi versus ID4-EGFP + / TSPAN8-Lo spermatogonia (Mutoji et al, 2016); upregulated genes in THY1 + spermatogonia versus KIT + (differentiating) spermatogonia (Hammoud et al, 2015); and upregulated genes in ID4-EGFP Bright versus ID4-EGFP Dim spermatogonia (Fig. S4).…”

Section: Discussionmentioning

confidence: 99%

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ID4 levels dictate the stem cell state in mouse spermatogonia

et al. 2017

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Spermatogenesis is a classic model of cycling cell lineages that depend on a balance between stem cell self-renewal for continuity and the formation of progenitors as the initial step in the production of differentiated cells. The mechanisms that guide the continuum of spermatogonial stem cell (SSC) to progenitor spermatogonial transition and precise identifiers of subtypes in the process are undefined. Here we used an Id4-eGfp reporter mouse to discover that EGFP intensity is predictive of the subsets, with the ID4-EGFP Bright population being mostly, if not purely, SSCs, whereas the ID4-EGFP Dim population is in transition to the progenitor state. These subsets are also distinguishable by transcriptome signatures. Moreover, using a conditional overexpression mouse model, we found that transition from the stem cell to the immediate progenitor state requires downregulation of Id4 coincident with a major change in the transcriptome. Collectively, our results demonstrate that the level of ID4 is predictive of stem cell or progenitor capacity in spermatogonia and dictates the interface of transition between the different functional states.

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“…Further, Sun et al (2015) used lineage tracing techniques to independently establish that at least a portion of the ID4-expressing spermatogonial population possess long-term self-renewal capacity in vivo , in both neonatal and adult testes. While the ID4+ spermatogonial population as a whole is highly enriched for SSCs, it is important to note that heterogeneity exists even within this pool of cells; as depicted by a spectrum of ID4-eGFP fluorescence (bright to dim) (Chan et al 2014, Helsel et al 2017), and the differential expression of factors such as TSPAN8 (Mutoji et al 2016). The significance of heterogeneity in terms of levels of ID4 expression will be discussed briefly in the context of the A single model.…”

Section: Approaches For Studying Ssc Dynamicsmentioning

confidence: 99%

A revised Asingle model to explain stem cell dynamics in the mouse male germline

Lord

Oatley

2017

Reproduction

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Spermatogonial stem cells (SSCs) and progenitor spermatogonia encompass the undifferentiated spermatogonial pool in mammalian testes. In rodents, this population is comprised of Asingle, Apaired, and chains of 4–16 Aaligned spermatogonia. While traditional models propose that the entire Asingle pool represents the SSCs, and formation of an Apaired syncytium symbolizes irreversible entry to a progenitor state destined for differentiation; recent models have emerged that suggest the Asingle pool is heterogeneous, and Apaired/Aaligned can fragment to produce new SSCs. In this review, we explore evidence from the literature for these differing models representing SSC dynamics; including the traditional ‘Asingle’, and more recently formed ‘fragmentation’ model. Further, based on findings using a fluorescent reporter transgene (eGfp) that reflects expression of the SSC-specific transcription factor ‘Inhibitor of DNA binding 4’ (Id4), we propose a revised version of the traditional model in which SSCs are a subset of the Asingle population; the ID4-eGFP bright cells (SSCultimate). From the SSCultimate pool, other Asingle and Apaired cohorts arise that are ID4-eGFP dim. While the SSCultimate possess a transcriptome profile that reflects a self-renewing state, the transcriptome of the ID4-eGFP dim population resembles that of cells in transition to a progenitor state (SSCtransitory). Accordingly, at the next mitotic division, these SSCtransitory are likely to join the progenitor pool and have lost stem cell capacity. This model supports the concept of a linear relationship between spermatogonial chain length and propensity for differentiation, while leaving open the possibility that the SSCtransitory (some Asingle and potentially some Apaired spermatogonia), may contribute to the self-renewing pool rather than transition to a progenitor state in response to perturbations of steady-state conditions.

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TSPAN8 Expression Distinguishes Spermatogonial Stem Cells in the Prepubertal Mouse Testis

Cited by 35 publications

References 75 publications

The Mammalian Spermatogenesis Single-Cell Transcriptome, from Spermatogonial Stem Cells to Spermatids

The Mammalian Spermatogenesis Single-Cell Transcriptome, from Spermatogonial Stem Cells to Spermatids

ID4 levels dictate the stem cell state in mouse spermatogonia

A revised Asingle model to explain stem cell dynamics in the mouse male germline

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