Dataset Information

TSPAN8 Expression Distinguishes Spermatogonial Stem Cells in the Prepubertal Mouse Testis.

ABSTRACT: Precise separation of spermatogonial stem cells (SSCs) from progenitor spermatogonia that lack stem cell activity and are committed to differentiation remains a challenge. To distinguish between these spermatogonial subtypes, we identified genes that exhibited bimodal mRNA levels at the single-cell level among undifferentiated spermatogonia from Postnatal Day 6 mouse testes, including Tspan8, Epha2, and Pvr, each of which encode cell surface proteins useful for cell selection. Transplantation studies provided definitive evidence that a TSPAN8-high subpopulation is enriched for SSCs. RNA-seq analyses identified genes differentially expressed between TSPAN8-high and -low subpopulations that clustered into multiple biological pathways potentially involved in SSC renewal or differentiation, respectively. Methyl-seq analysis identified hypomethylated domains in the promoters of these genes in both subpopulations that colocalized with peaks of histone modifications defined by ChIP-seq analysis. Taken together, these results demonstrate functional heterogeneity among mouse undifferentiated spermatogonia and point to key biological characteristics that distinguish SSCs from progenitor spermatogonia.

SUBMITTER: Mutoji K

PROVIDER: S-EPMC5315423 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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TSPAN8 Expression Distinguishes Spermatogonial Stem Cells in the Prepubertal Mouse Testis.

Mutoji Kazadi K Singh Anukriti A Nguyen Thu T Gildersleeve Heidi H Kaucher Amy V AV Oatley Melissa J MJ Oatley Jon M JM Velte Ellen K EK Geyer Christopher B CB Cheng Keren K McCarrey John R JR Hermann Brian P BP

Biology of reproduction 20161012 6

Precise separation of spermatogonial stem cells (SSCs) from progenitor spermatogonia that lack stem cell activity and are committed to differentiation remains a challenge. To distinguish between these spermatogonial subtypes, we identified genes that exhibited bimodal mRNA levels at the single-cell level among undifferentiated spermatogonia from Postnatal Day 6 mouse testes, including Tspan8, Epha2, and Pvr, each of which encode cell surface proteins useful for cell selection. Transplantation st ...[more]

PMID: 27733379

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Project description:Graphical abstract Highlights • Background: The risk of infertility after chemotherapy is unpredictable in children with cancer.• Our in vitro study demonstrated short-term damage of chemotherapy on immature mouse testis.• Cisplatin and doxorubicin induce acute spermatogonial stem cell loss that does not persist two months later.• High concentrations of cisplatin impair later phases of spermatogenesis in the long-term. Chemotherapy can affect testis development of young boys with cancer, reducing the chances of fatherhood in adulthood. Studies using experimental models are needed to determine the damage caused by individual chemotherapy drugs in order to predict the risk of infertility and direct patients towards appropriate fertility preservation options. Here, we investigated the individual role of two drugs, cisplatin and doxorubicin, using an in vitro culture model of prepubertal (postnatal day 5) mouse testis that supports induction and maintenance of full spermatogenesis. Twenty-four hour exposure with either drug at clinically-relevant doses (0.25, 0.5 or 0.75 ?g/mL for cisplatin, or 0.01, 0.03 or 0.05 ?g/mL for doxorubicin), induced an acute significant loss of spermatogonial stem cells (SSCs; PLZF+), proliferating SSCs (PLZF+BrdU+), total germ cells (MVH+), and spermatocytes (SCP3+) one week after chemotherapy exposure. By the time of the first (Week 4) and second (Week 8) waves of spermatogenesis, there was no longer any effect on SSC or proliferating SSC numbers in drug-exposed testis compared to untreated tissue: however, the populations of total germ cells and spermatocytes were still lower in the higher-dose cisplatin treated groups, along with a reduced frequency of round and elongated spermatids in both cisplatin- and doxorubicin-treated testis fragments. Overall, this study details a direct impairment of germ cell development following acute chemotherapy-induced damage during the prepubertal phase, most likely due to an effect on SSCs, using an in vitro culture system that successfully recapitulates key events of mouse spermatogenesis.

Dataset Information

TSPAN8 Expression Distinguishes Spermatogonial Stem Cells in the Prepubertal Mouse Testis.

Publications

TSPAN8 Expression Distinguishes Spermatogonial Stem Cells in the Prepubertal Mouse Testis.

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