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Stem Leydig cells: An Effective Stem Cell Treatment for Testosterone Deficiency?

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Review of “Transplantation of CD51+ Stem Leydig Cells - A New Strategy for the Treatment of Testosterone Deficiency” from STEM CELLS by Stuart P. Atkinson

Treatment of testosterone deficiency with long-term testosterone therapy [1] involves certain risks and complications [2] and many researchers have now turned to stem cell research to develop safer and more efficient treatment options. Stem Leydig cells (SLCs) can proliferate and differentiate into testosterone-producing Leydig cells (LCs) of the testicular interstitium [3] and, so, SLC transplantation may have the capacity to replace testosterone therapy [4]. However, isolating rare SLCs from the adult testes remains difficult due, in part, to a lack of specific cell markers.

A previous study from the labs of Mei Hua Jiang and Andy Peng Xiang (Sun Yat-sen University, Guangzhou, Guangdong, China) described CD51 (also called integrin αv) as a potentially useful marker of SLCs in mice [5]. Now, Zang et al demonstrate that CD51-sorted SLCs can restore testosterone production and promote recovery of spermatogenesis in a testosterone deficiency rat model [6]. This encouraging new finding suggests that SLC transplantation may represent a safe and effective treatment for human patients [7]. 

Initial analyses of CD51+ cells isolated from 12-weeks-old mouse testes established that putative SLCs expressed known SLC lineage markers, proliferated extensively in vitro, and displayed self-renewal capabilities. Furthermore, CD51+ cells demonstrated multilineage potential, forming cells of the osteogenic, adipogenic and chondrogenic lineage, as well as mature testosterone-synthesizing LCs.

Encouragingly, the intratesticular transplantation of CD51+ SLCs in a testosterone deficiency rat model mediated a gradual increase in serum testosterone levels. Furthermore, transplanted mice displayed the normal daily rhythm of testosterone secretion and appropriate testosterone level regulation by the hypothalamic-pituitary-gonadal (HPG) axis. Finally, and perhaps most importantly, CD51+ SLC transplantation also reversed the loss of reproductive organ weight observed after testosterone loss and promoted the production of sperm.

This exciting study suggests that CD51+ cells represent stem Leydig cells and that their transplantation may provide a promising and side effect-free treatment option for human testosterone deficiency patients. Achieving this goal will require the study to proceed from rats and mice to man and the derivation of CD51+ SLCs from human patients and/or the generation of SLCs from patient-specific induced pluripotent stem cells (iPSCs). 

Stay tuned to the Stem Cells Portal to find out if SLCs will soon represent an effective stem cell treatment for testosterone deficiency.

Discussion Points

  • Do SLCs survive and function over longer periods or will repeated transplants be required?
  • Will CD51+ prove successful for the isolation of human SLCs?
  • What factors are likely to be involved in the generation of SLCs from pluripotent stem cell sources?

References

  1. Allan CA and McLachlan RI. Age-related changes in testosterone and the role of replacement therapy in older men. Clinical endocrinology 2004;60:653-670.
  2. Traish AM. Adverse health effects of testosterone deficiency (TD) in men. Steroids 2014;88:106-116.
  3. Stanley E, Lin CY, Jin S, et al. Identification, proliferation, and differentiation of adult Leydig stem cells. Endocrinology 2012;153:5002-5010.
  4. Yang Y, Su Z, Xu W, et al. Directed mouse embryonic stem cells into leydig-like cells rescue testosterone-deficient male rats in vivo. Stem Cells Dev 2015;24:459-470.
  5. Jiang MH, Cai B, Tuo Y, et al. Characterization of Nestin-positive stem Leydig cells as a potential source for the treatment of testicular Leydig cell dysfunction. Cell Res 2014;24:1466-1485.
  6. Morris ID, Phillips DM, and Bardin CW. Ethylene dimethanesulfonate destroys Leydig cells in the rat testis. Endocrinology 1986;118:709-719.
  7. Zang ZJ, Wang J, Chen Z, et al. Transplantation of CD51+ Stem Leydig Cells: A New Strategy for the Treatment of Testosterone Deficiency. STEM CELLS 2017;35:1222-1232.