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

Stem Leydig cell (SLC) transplantation could provide a new strategy for treating the testosterone deficiency. Our previous study demonstrated that CD51 (also called integrin [alpha]v) might be a putative cell surface marker for SLCs, but the physiological function and efficacy of CD51 super(+) SLCs treatment remain unclear. Here, we explore the potential therapeutic benefits of CD51 super(+) SLCs transplantation and whether these transplanted cells can be regulated by the hypothalamic-pituitary-gonadal (HPG) axis. CD51 super(+) 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 super(+) 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 super(+) 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 Isolated CD51 super(+) cells from the testes of adult mice have SLCs properties in vitro, including self-renew and multiple differentiation. After transplantation, the CD51 super(+) SLCs can differentiate to mature LCs, be regulated by the hypothalamic-pituitary-gonadal axis and restore testosterone production with circadian rhythm.