Restorative functions of Autologous Stem Leydig Cell transplantation in a Testosterone-deficient non-human primate model

Abstract

Rationale: Stem Leydig cells (SLCs) transplantation can restore testosterone production in rodent models and is thus a potential solution for treating testosterone deficiency (TD). However, it remains unknown whether these favorable effects will be reproduced in more clinically relevant large-animal models. Therefore, we assessed the feasibility, safety and efficacy of autologous SLCs transplantation in a testosterone-deficient non-human primate (NHP) model. Methods: Cynomolgus monkey SLCs (CM-SLCs) were isolated from testis biopsies of elderly (> 19 years) cynomolgus monkeys by flow cytometry. Autologous CM-SLCs were injected into the testicular interstitium of 7 monkeys. Another 4 monkeys were injected the same way with cynomolgus monkey dermal fibroblasts (CM-DFs) as controls. The animals were then examined for sex hormones, semen, body composition, grip strength, and exercise activity. Results: We first isolated CD271 + CM-SLCs which were confirmed to expand continuously and show potential to differentiate into testosterone-producing Leydig cells (LCs) in vitro . Compared with CM-DFs transplantation, engraftment of autologous CM-SLCs into elderly monkeys could significantly increase the serum testosterone level in a physiological pattern for 8 weeks, without any need for immunosuppression. Importantly, CM-SLCs transplantation recovered spermatogenesis and ameliorated TD-related symptoms, such as those related to body fat mass, lean mass, bone mineral density, strength and exercise capacity. Conclusion: For the first time, our short-term observations demonstrated that autologous SLCs can increase testosterone levels and ameliorate relevant TD symptoms in primate models. A larger cohort with long-term follow-up will be required to assess the translational potential of autologous SLCs for TD therapy.

ICA II Alleviates Testicular Torsion Injury by Dampening the Oxidative and Inflammatory Stress

“…Johnsen’s score was significantly higher in ICA II-treated group compared to the saline group ( Figure 1B ). Sertoli cells is essential for spermatogenesis ( 24 ). To verify whether ICA II had a beneficial effect on the maintenance of the spermatogenesis environment, we examined the expression of the Sertoli cell marker SOX9 ( 25 , 26 ).…”

Generation of Leydig-like cells: approaches, characterization, and challenges

“…In a primate model, Cynomolgus monkey SLCs (CM-SLCs) were isolated based on the cell surface marker CD271 + . 38 After proliferation in vitro with the conventional cultivation method, CM-SLCs were transplanted back into the interstitium of the testis, and the cells were able to colonize, differentiate, and integrate into the host microenvironment. More importantly, CM-SLC transplantation significantly increased the serum testosterone level in a physiological pattern, recovered spermatogenesis, and ameliorated TD-related symptoms in elderly monkeys.…”

Sex and Regeneration

“…Another example of sex steroid hormones’ role in stem cell activity is in mice cardiac stem cells by increasing proliferation, improving telomerase activity, and reducing DNA damage [ 51 ]. Castration of male mice leads to increased longevity of stem cells [ 21 , 52 ]. It seems that in multicellular animal models, stem cell performance (or regeneration) decreases with age and sexual maturity that go together.…”