Ying ZK, Xu XY, Hu JW, Cui Y, Jiang DW. Single-cell transcriptomics reveals a spermatogonial stem cell-centered spermatogenic microenvironment: Pathophysiological mechanisms and therapeutic targets in male infertility. World J Stem Cells 2026; 18(3): 118401 [DOI: 10.4252/wjsc.v18.i3.118401]
Corresponding Author of This Article
Da-Wei Jiang, PhD, Department of Andrology, Jiaxing Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, No. 1501 Zhongshan East Road, Nanhu District, Jiaxing 314001, Zhejiang Province, China. yush1128@yeah.net
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Andrology
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Mar 26, 2026 (publication date) through Mar 28, 2026
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World Journal of Stem Cells
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1948-0210
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Ying ZK, Xu XY, Hu JW, Cui Y, Jiang DW. Single-cell transcriptomics reveals a spermatogonial stem cell-centered spermatogenic microenvironment: Pathophysiological mechanisms and therapeutic targets in male infertility. World J Stem Cells 2026; 18(3): 118401 [DOI: 10.4252/wjsc.v18.i3.118401]
World J Stem Cells. Mar 26, 2026; 18(3): 118401 Published online Mar 26, 2026. doi: 10.4252/wjsc.v18.i3.118401
Single-cell transcriptomics reveals a spermatogonial stem cell-centered spermatogenic microenvironment: Pathophysiological mechanisms and therapeutic targets in male infertility
Zhi-Kang Ying, Jia-Wei Hu, Department of Andrology, Zhejiang Chinese Medical University Graduate Ningbo Joint Training Base, Ningbo 315010, Zhejiang Province, China
Zhi-Kang Ying, Jia-Wei Hu, Yun Cui, Department of Andrology, Ningbo Municipal Hospital of Traditional Chinese Medicine, Affiliated Hospital of Zhejiang Chinese Medical University, Ningbo 315010, Zhejiang Province, China
Xin-Yu Xu, Department of Urology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
Da-Wei Jiang, Department of Andrology, Jiaxing Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Jiaxing 314001, Zhejiang Province, China
Author contributions: Jiang DW conceptualized and designed the study; Ying ZK developed the methodology and drafted the manuscript; Xu XY and Hu JW conducted the literature search; Cui Y created the figures and tables. All authors have read and approved the final manuscript. Jiaxing Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University serves as the primary affiliation for this article.
Supported by Jiaxing Municipal Health Science and Technology Plan Key Project, No. JWKD-25010; and the Special Scientific Research Project of the Affiliated Hospital of Zhejiang Chinese Medical University, No. 2024FSYYZQ17.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Corresponding author: Da-Wei Jiang, PhD, Department of Andrology, Jiaxing Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, No. 1501 Zhongshan East Road, Nanhu District, Jiaxing 314001, Zhejiang Province, China. yush1128@yeah.net
Received: December 31, 2025 Revised: January 22, 2026 Accepted: March 9, 2026 Published online: March 26, 2026 Processing time: 84 Days and 15.7 Hours
Abstract
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.
Core Tip: This review integrates single-cell transcriptomics data from 2018 to 2025 to reconstruct the pathological landscape of male infertility, identifying the spermatogonial stem cell niche as a core therapeutic target. We elucidate a novel mechanistic axis linking “inflammaging” and NLRP3 inflammasome activation to spermatogonial stem cell depletion in non-obstructive azoospermia. Furthermore, we critically evaluate translational barriers, including geographic data bias and technical limitations, and propose a precision medicine framework integrating multiethnic cohorts to bridge the gap between single-cell atlases and clinical andrology.
