Subcutaneous Leydig Stem Cell Autograft: A Promising Strategy to Increase Serum Testosterone

摘要

Exogenous testosterone therapy can be used to treat testosterone deficiency; however, it hasseveral adverse effects including infertility due to negative feedback on the hypothalamic–pituitary–gonadal (HPG) axis. Leydig stem cell (LSC) transplantation could provide a new strategyfor treating testosterone deficiency, but clinical translatability of injecting stem cells insidethe testis is not feasible. Here, we explore the feasibility of subcutaneously autografting LSCsin combination with Sertoli and myoid cells to increase testosterone. We also studied whetherthe grafted LSCs can be regulated by the HPG axis and the molecular mechanism behind thisregulation. LSCs were isolated from the testes of 12-week-old C57BL/6 mice, and subcutaneouslyautografted in combination with Sertoli cells and myoid cells. We found that LSCs alonewere incapable of self-renewal and differentiation. However, in combination with Sertoli cellsand myoid cells, LSCs underwent self-renewal as well as differentiation into mature Leydigcells. As a result, the recipient mice that received the LSC autograft showed testosterone productionwith preserved luteinizing hormone. We found that testosterone production from theautograft was regulated by hedgehog (HH) signaling. Gain of function and loss of functionstudy confirmed that Desert HH (DHH) agonist increased and DHH antagonist decreased testosteroneproduction from autograft. This study is the first to demonstrate that LSCs, whenautografted subcutaneously in combination with Sertoli cells and myoid cells, can increase testosteroneproduction. Therefore, LSC autograft may provide a new treatment for testosteronedeficiency while simultaneously preserving the HPG axis.