Cell Reports
Volume 17, Issue 10, 6 December 2016, Pages 2789-2804
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In Vitro Derivation and Propagation of Spermatogonial Stem Cell Activity from Mouse Pluripotent Stem Cells

https://doi.org/10.1016/j.celrep.2016.11.026Get rights and content
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Highlights

  • In vitro derivation of mouse germline stem cell-like cells (GSCLCs) from ESCs

  • GSCLCs colonize adult testes and contribute to spermatogenesis and fertile offspring

  • GSCLCs show aberrant DNA methylation at vulnerable regulatory elements

  • Spermatogonial stem cell induction relies on faithful regulation of DNA methylation

Summary

The in vitro derivation and propagation of spermatogonial stem cells (SSCs) from pluripotent stem cells (PSCs) is a key goal in reproductive science. We show here that when aggregated with embryonic testicular somatic cells (reconstituted testes), primordial germ cell-like cells (PGCLCs) induced from mouse embryonic stem cells differentiate into spermatogonia-like cells in vitro and are expandable as cells that resemble germline stem cells (GSCs), a primary cell line with SSC activity. Remarkably, GSC-like cells (GSCLCs), but not PGCLCs, colonize adult testes and, albeit less effectively than GSCs, contribute to spermatogenesis and fertile offspring. Whole-genome analyses reveal that GSCLCs exhibit aberrant methylation at vulnerable regulatory elements, including those critical for spermatogenesis, which may restrain their spermatogenic potential. Our study establishes a strategy for the in vitro derivation of SSC activity from PSCs, which, we propose, relies on faithful epigenomic regulation.

Keywords

spermatogonial stem cells
embryonic stem cells
primordial germ cells
testes
DNA methylation
epigenetic reprogramming

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