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Single-cell transcriptomics reveals a spermatogonial stem cell-centered spermatogenic microenvironment: Pathophysiological mechanisms and therapeutic targets in male infertility
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DOI：10.4252/wjsc.v18.i3.118401.png)
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Abstract
En 中文
Male infertility affects approximately 17.5% of the global reproductive-age population, with disruption of the testicular spermatogenic microenvironment - particularly the spermatogonial stem cell niche - representing a central pathogenic mechanism. Single-cell RNA sequencing has enabled unprecedented resolution of cellular heterogeneity within the human testis; however, its translational value remains constrained by population data imbalance and limited integration across molecular layers. Here, we synthesize single-cell RNA sequencing studies published between January 2018 and September 2025 to construct a microenvironment-centered mechanistic framework linking inflammaging, NLRP3 inflammasome activation, and progressive spermatogonial stem cell depletion in non-obstructive azoospermia, supported by convergent single-cell, bulk transcriptomic, and emerging preclinical evidence. We further discuss transgenerational epigenetic effects mediated by sperm small non-coding RNAs and critically evaluate translational barriers, including ancestry bias, technical limitations of single-cell platforms, and ethical challenges of germline intervention. We propose that future clinical translation will require multiethnic cohort construction and artificial intelligence-driven multi-omics integration to enable stem cell-oriented precision diagnosis and therapy for male infertility.
Keywords:
Single-cell transcriptomics
Spermatogonial stem cell
Testicular microenvironment
Male infertility
NLRP3 inflammasome
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