Male factor infertility affects 50% of infertile couples worldwide; the most severe form, non-obstructive azoospermia (NOA), affects 10-15% of infertile males. Treatment for individuals with NOA is limited to microsurgical sperm extraction paired with in vitro fertilization intracytoplasmic sperm injection. Unfortunately, spermatozoa are only retrieved in ~50% of patients, resulting in live birth rates of 21-46%. Regenerative therapies could provide a solution; however, understanding the cell-type-specific mechanisms of cellular dysfunction is a fundamental necessity to develop precision medicine strategies that could overcome these abnormalities and promote regeneration of spermatogenesis. A number of mechanisms of cellular dysfunction have been elucidated in NOA testicular cells. These mechanisms include abnormalities in both somatic cells and germ cells in NOA testes, such as somatic cell immaturity, aberrant growth factor signalling, increased inflammation, increased apoptosis and abnormal extracellular matrix regulation. Future cell-type-specific investigations in identifying modulators of cellular transcription and translation will be key to understanding upstream dysregulation, and these studies will require development of in vitro models to functionally interrogate spermatogenic niche dysfunction in both somatic and germ cells.
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