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Molecular gatekeepers balancing differentiation and maintenance of human male germline stem cells uncovered by single cell resolution analysis

ABSTRACT: Human male germline homeostasis depends on a balance between differentiation and maintenance of spermatogonial stem cells. To unveil the molecular regulation of this balance we compared human testicular tissues with severely perturbed germ cell differentiation with the normal situation. By performing single cell RNA sequencing of close to 30.000 cells and histomorphometric analysis we demonstrate that the proportion of spermatogonia remains remarkably stable despite the dwindling numbers of differentiated germ cells. In spite of this, these samples displayed altered stem cell dynamics with a push of reserve stem cells towards differentiation. This shift in dynamics was associated with the activation of gene networks regulated by four main gatekeeping transcription factors: ASCL2, EGR4, HOXC9, and DLX5. We provide invaluable information on the pathways regulating human germline stem cell dynamics along with evidence for a striking depletion of the reserve stem cell pool when these are disturbed.

ORGANISM(S): Homo sapiens

PROVIDER: GSE153947 | GEO | 2021/09/08

REPOSITORIES: GEO

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Project description:In regenerative medicine, histocompatibility of pluripotent stem cells is required to solve the problem of immunorejection after therapeutic transplantation. In this study, we show that autologous germline stem cells (GSCs), often called spermatogonial stem cells, could be derived by testis biopsy from individual mice and that GSCs subsequently could be dedifferentiated into autologous germline-derived pluripotent stem (gPS) cells. The establishment of GSCs by testicular biopsy in the mouse model can prove the principle of human clinical application to derive autologous GSCs to generate patient-specific pluripotent cells for regenerative medicine. For transcriptome profiling, 400 ng of total DNA-free RNA was used as input for labelled cRNA synthesis (Illumina TotalPrep RNA Amplification Kit - Ambion) following the manufacturer's instructions (IVT: 12h). Quality-checked cRNA samples were hybridized as biological or technical duplicates for 18 h onto mouse-8 v2 expression BeadChips (Illumina), washed, stained, and scanned following guidelines and using materials / instrumentation supplied / suggested by the manufacturer 13 samples were analyzed, GSC1: Mouse Germ Stem Cells OG2, line 1 (1 replicate); GSC2: Mouse Germ Stem Cells OG2, line 2 (1 replicate); GSC3: Mouse Germ Stem Cells OG2, line 3 (1 replicate); GSCr1: Mouse Germ Stem Cells OG2-ROSA, line 1 (1 replicate); GSCr2: Mouse Germ Stem Cells OG2-ROSA, line 2 (2 replicate); GSCr3: Mouse Germ Stem Cells OG2-ROSA, line 3 (1 replicate); ESC: Mouse Embryonic Stem Cells (duplicate) gPS1: Mouse clonal germ Pluripotent Stem cells from OG2, line 1, (1 replicate); gPS2: Mouse clonal germ Pluripotent Stem cells from OG2, line 2, (1 replicate); gPS3: Mouse clonal germ Pluripotent Stem cells from OG2, line 3, (1 replicate); gPSr1: Mouse clonal germ Pluripotent Stem cells from OG2-ROSA, line 1, (1 replicate); gPSr2: Mouse clonal germ Pluripotent Stem cells from OG2-ROSA, line 2, (1 replicate); gPSr3: Mouse clonal germ Pluripotent Stem cells from OG2-ROSA, line 3, (1 replicate).

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Molecular gatekeepers balancing differentiation and maintenance of human male germline stem cells uncovered by single cell resolution analysis

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