Transplantation of CD51+ Stem Leydig Cells: A New Strategy for the Treatment of Testosterone Deficiency

Abstract

Stem Leydig cell (SLC) transplantation could provide a new strategy for treating the testosterone deficiency. Our previous study demonstrated that CD51 (also called integrin αv) might be a putative cell surface marker for SLCs, but the physiological function and efficacy of CD51 SLCs treatment remain unclear. Here, we explore the potential therapeutic benefits of CD51 SLCs transplantation and whether these transplanted cells can be regulated by the hypothalamic-pituitary-gonadal (HPG) axis. CD51 cells were isolated from the testes of 12-weeks-old C57BL/6 mice, and we showed that such cells expressed SLC markers and that they were capable of self-renewal, extensive proliferation, and differentiation into multiple mesenchymal cell lineages and LCs in vitro. As a specific cytotoxin that eliminates Leydig cells (LCs) in adult rats, ethane dimethanesulfonate (EDS) was used to ablate LCs before the SLC transplantation. After being transplanted into the testes of EDS-treated rats, the CD51 cells differentiated into mature LCs, and the recipient rats showed a partial recovery of testosterone production and spermatogenesis. Notably, a testosterone analysis revealed a circadian rhythm of testosterone secretion in cell-transplanted rats, and these testosterone secretions could be suppressed by decapeptyl (a luteinizing hormone-releasing hormone agonist), suggesting that the transplanted cells might be regulated by the HPG axis. This study is the first to demonstrate that CD51 SLCs can restore the neuroendocrine regulation of testicular function by physiologically recovering the expected episodic changes in diurnal testosterone serum levels and that SLC transplantation may provide a new tool for the studies of testosterone deficiency treatment. Stem Cells 2017;35:1222-1232.

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

“…In contrast, negative control animals that received matrigel alone lacked any ALCs. The presence of differentiation in LCs in autografts was confirmed by immunofluorescence (IF) which stained ALCs positively for 3BHSD, STAR, and LHR (marker of LC) (Fig. D).…”

Insights into the Development of the Adult Leydig Cell Lineage from Stem Leydig Cells

“…Interestingly, nestin-positive SLCs also express CD51, a biomarker for the mesenchymal stem cells (Rux et al, 2016). Like nestin-positive cells, CD51-positive cells are also able to self-renew and differentiate into the multiple mesenchymal cell lineages and ALCs in vitro , as well as to clone back in the testicular niche (Table 1; Zang et al, 2017). This suggests that CD51-positive SLCs are multipotent.…”

A Preview of Selected Articles

“…Thus, the authors assessed the utility of another marker identified in this study, CD51 (also called integrin αv), as a putative cell surface marker for adult mouse LSCs, and subsequently evaluated testes transplantation of purified LSCs as a means to treat testosterone deficiency. In their Stem Cells article , Zang et al first demonstrated the in vitro self‐renewal capacity of CD51‐positive cells, as well as their ability to differentiate into mesenchymal lineage cells and LCs. Following in vivo ablation of rat LCs via ethane dimethanesulfonate treatment and the transplantation of CD51+ LSCs in the rat testes, the authors observed the differentiation of LSCs into mature LCs and recovery of both testosterone production (with circadian rhythm) and spermatogenesis, and, encouragingly, the transplanted cells also displayed regulation by the HPG axis.…”

“…In our second Featured Article from Stem Cells Translational Medicine , Arora et al describe how subcutaneous autografting of LSCs in combination with Sertoli cells and myoid cells can increase testosterone production in castrated mice, thereby providing a potentially exciting new treatment for testosterone deficiency. In a Related Article published in Stem Cells , Zang et al report on the prospective isolation of LSCs from the testes of adult mice employing a cell surface marker and their exploration of LSC transplantation into the testes as a therapy for testosterone deficiency.…”