Figure 2. Standard and experimental options to treat male factor infertility. (A) Sperm obtained from ejaculated semen or by testicular sperm extraction (TESE) of infertile men can be used to achieve pregnancy by intrauterine insemination (IUI), in vitro fertilization (IVF), or IVF with intracytoplasmic sperm injection (ICSI). (B) When it is not possible to obtain sperm, testicular tissue containing spermatogonial stem cells (SSCs) can be obtained by biopsy. Testicular tissue can be digested with enzymes to produce a cell suspension from which spermatogonial stem cells can be expanded in culture and/or transplanted into the testes of the patient. This method has the potential to regenerate spermatogenesis and possibly natural fertility. Heterogeneous testicular cell suspensions also have the potential to undergo de novo testicular morphogenesis to produce seminiferous tubules with a polarized epithelium surrounded by a basement membrane with germ cells inside and interstitial cells outside the tubules. Sperm generated in the “rebuilt” testes can be used to fertilize eggs by ICSI. Intact testicular tissues from prepubertal males can be grafted or xenografted under the skin or in the scrotum and produce mature sperm that can be used to fertilize eggs by ICSI. Sperm can also be generated when immature testicular tissues are maintained in organ culture and used to fertilize eggs by ICSI. (C) Patient-specific induced pluripotent stem (iPS) cells can be derived from patient somatic tissues (e.g., skin or blood) and differentiated into germ line stem cells (GSCs) to be transplanted into patient testes. This method may have the potential to regenerate spermatogenesis and natural fertility. It may also be possible to differentiate induced pluripotent stem cells into sperm that can be used to fertilize eggs by ICSI.