Impact of restoring male fertility with transplantation of in vitro propagated spermatogonial stem cells on the health of their offspring throughout life

Clinical and Translational MedicineVolume 11, Issue 10 e531 LETTER TO EDITOROpen Access Impact of restoring male fertility with transplantation of in vitro propagated spermatogonial stem cells on the health of their offspring throughout life Joana B. Serrano, Joana B. Serrano orcid.org/0000-0003-3702-3727 Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC, Amsterdam Reproduction and Development Research Institute, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorRik van Eekelen, Rik van Eekelen Center for Reproductive Medicine, Amsterdam UMC, Amsterdam Reproduction and Development Research Institute, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorCindy M. de Winter-Korver, Cindy M. de Winter-Korver Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC, Amsterdam Reproduction and Development Research Institute, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorSaskia K.M. van Daalen, Saskia K.M. van Daalen Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC, Amsterdam Reproduction and Development Research Institute, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorNils C. Tabeling, Nils C. Tabeling Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC, Amsterdam Reproduction and Development Research Institute, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorLisa A.E. Catsburg, Lisa A.E. Catsburg Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC, Amsterdam Reproduction and Development Research Institute, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorMarion J.J. Gijbels, Marion J.J. Gijbels Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands Department of Pathology CARIM, Cardiovascular Research Institute Maastricht, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The NetherlandsSearch for more papers by this authorCallista L. Mulder, Corresponding Author Callista L. Mulder c.l.mulder@amsterdamumc.nl Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC, Amsterdam Reproduction and Development Research Institute, University of Amsterdam, Amsterdam, The Netherlands Both the authors contributed equally to this work as co-senior authors. Correspondence Callista L. Mulder and Ans M.M. van Pelt, Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC, Amsterdam Reproduction and Development Research Institute, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. Email: a.m.vanpelt@amsterdamumc.nl and c.l.mulder@amsterdamumc.nlSearch for more papers by this authorAns M.M. van Pelt, Corresponding Author Ans M.M. van Pelt a.m.vanpelt@amsterdamumc.nl orcid.org/0000-0001-9155-548X Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC, Amsterdam Reproduction and Development Research Institute, University of Amsterdam, Amsterdam, The Netherlands Both the authors contributed equally to this work as co-senior authors. Correspondence Callista L. Mulder and Ans M.M. van Pelt, Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC, Amsterdam Reproduction and Development Research Institute, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. Email: a.m.vanpelt@amsterdamumc.nl and c.l.mulder@amsterdamumc.nlSearch for more papers by this author Joana B. Serrano, Joana B. Serrano orcid.org/0000-0003-3702-3727 Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC, Amsterdam Reproduction and Development Research Institute, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorRik van Eekelen, Rik van Eekelen Center for Reproductive Medicine, Amsterdam UMC, Amsterdam Reproduction and Development Research Institute, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorCindy M. de Winter-Korver, Cindy M. de Winter-Korver Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC, Amsterdam Reproduction and Development Research Institute, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorSaskia K.M. van Daalen, Saskia K.M. van Daalen Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC, Amsterdam Reproduction and Development Research Institute, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorNils C. Tabeling, Nils C. Tabeling Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC, Amsterdam Reproduction and Development Research Institute, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorLisa A.E. Catsburg, Lisa A.E. Catsburg Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC, Amsterdam Reproduction and Development Research Institute, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorMarion J.J. Gijbels, Marion J.J. Gijbels Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands Department of Pathology CARIM, Cardiovascular Research Institute Maastricht, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The NetherlandsSearch for more papers by this authorCallista L. Mulder, Corresponding Author Callista L. Mulder c.l.mulder@amsterdamumc.nl Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC, Amsterdam Reproduction and Development Research Institute, University of Amsterdam, Amsterdam, The Netherlands Both the authors contributed equally to this work as co-senior authors. Correspondence Callista L. Mulder and Ans M.M. van Pelt, Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC, Amsterdam Reproduction and Development Research Institute, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. Email: a.m.vanpelt@amsterdamumc.nl and c.l.mulder@amsterdamumc.nlSearch for more papers by this authorAns M.M. van Pelt, Corresponding Author Ans M.M. van Pelt a.m.vanpelt@amsterdamumc.nl orcid.org/0000-0001-9155-548X Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC, Amsterdam Reproduction and Development Research Institute, University of Amsterdam, Amsterdam, The Netherlands Both the authors contributed equally to this work as co-senior authors. Correspondence Callista L. Mulder and Ans M.M. van Pelt, Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC, Amsterdam Reproduction and Development Research Institute, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. Email: a.m.vanpelt@amsterdamumc.nl and c.l.mulder@amsterdamumc.nlSearch for more papers by this author First published: 12 October 2021 https://doi.org/10.1002/ctm2.531 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Dear Editor, Spermatogonial stem cell transplantation (SSCT) is a potential novel fertility treatment for prepubertal cancer patients that require gonadotoxic treatment. It comprises in vitro propagation of SSCs from a cryopreserved testis biopsy followed by autotransplantation into the infertile patient's adult testis resulting in full recovery of spermatogenesis. In this blinded preclinical study, the long-term health of SSCT-derived offspring was assessed for the first time, using a systematic blueprint testing throughout life. No major differences in health outcomes between mice born after SSCT in two consecutive generations (first generation [F1] and second generation [F2]) and control were found, thereby providing crucial evidence that SSCT is a safe procedure. Due to its germline character, SSCT is the only adult stem cell-based transplantation therapy that can restore male fertility and may not only affect the recipient, but also the offspring. Remarkably, medically assisted reproductive (MAR) therapies have been introduced in the clinic after preclinical studies focusing mainly on its efficacy instead of safety for the offspring.1, 2 Unfortunately, after clinical implementation, children born after some of these MARs have increased risk for congenital abnormalities and low birthweight,3-6 developmental delays and cardiometabolic disease later in life.3, 4, 7 To ensure the health of future generations born from fathers that have received SSCT to restore fertility, we here studied indicators of health in the offspring throughout life that can be linked to potential risk factors of developmental problems, cardiometabolic disease, and ultimately result in increased mortality and pathologies2 (Supporting Information). Birth assessments showed that congenital abnormalities were a rare event (control n = 1/151, SSCT-F1 n = 3/125, SSCT-F2 n = 4/123; Figure 2A) with no statistically significant differences found in either SSCT generation compared to control (odds ratio [OR]: 3.78, 95% confidence interval [CI]: [0.14, 312.36]) for F1 and (OR: 4.18, 95% CI: [0.60, 82.90]) for F2 (Figure 2A), although the estimated odds ratios were relatively high.

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