Transient suppression of transplanted spermatogonial stem cell differentiation restores fertility in mice.

Yoshiaki Nakamura,David J. Jörg,Benjamin D. Simons,Shosei Yoshida,Yayoi Kon

doi:10.1016/j.stem.2021.03.016

Abstract

SummaryA remarkable feature of tissue stem cells is their ability to regenerate the structure and function of host tissue following transplantation. However, the dynamics of donor stem cells during regeneration remains largely unknown. Here we conducted quantitative clonal fate studies of transplanted mouse spermatogonial stem cells in host seminiferous tubules. We found that, after a large population of donor spermatogonia settle in host testes, through stochastic fate choice, only a small fraction persist and regenerate over the long term, and the rest are lost through differentiation and cell death. Further, based on these insights, we showed how repopulation efficiency can be increased to a level where the fertility of infertile hosts is restored by transiently suppressing differentiation using a chemical inhibitor of retinoic acid synthesis. These findings unlock a range of potential applications of spermatogonial transplantation, from fertility restoration in individuals with cancer to conservation of biological diversity.

Highlights

Tissue stem cells can restore the impaired structure and function of host tissues following transplantation
Post-transplantation fate analysis of GFRa1+ and Ngn3+ spermatogonia To resolve the identity of spermatogonial stem cell (SSC) that restore spermatogenesis following transplantation and to define their dynamics during repopulation, we performed quantitative clonal fate analysis of donor a small population of undifferentiated spermatogonia (Aundiff) in host testes of adult mice (Figures 1B–1I)
Single-cell suspensions prepared from donor testes were transplanted, without fractionation, into seminiferous tubules of adult host mice whose germ cells had been removed by busulfan treatment (Figure 1C)

Summary

Introduction

Tissue stem cells can restore the impaired structure and function of host tissues following transplantation. Spermatogonial stem cell (SSC) transplantation has been established in mice (Brinster and Avarbock, 1994; Brinster and Zimmermann, 1994; Figure S1A), promising a wealth of applications such as restoration of fertility of male individuals with cancer after chemotherapy or preservation of genetic diversity (Firlej et al, 2012; Honaramooz and Yang, 2010). Stem cell transplantation has been used for quantitative and functional assessment of stem cell potential (Brinster, 2002). Our knowledge of the fate behavior of individual SSCs and their progenies following transplantation remains poor, limiting the potential to develop new strategies to increase the currently low transplantation efficiencies

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Conclusion