Endothelial PDGF Signaling Dysregulation Impairs Testicular Interstitial Homeostasis in Diabetes

  • Adv Sci (Weinh). 2026 Apr;13(21):e20114. doi: 10.1002/advs.202520114.
Wenxiu Zhang  1  2  3 ,  Kai Hong  4 ,  Yanling Tang  4 ,  Lina Cui  1  2 ,  Xiaojian Lu  1  2 ,  Jianxing Cheng  4 ,  Yangyi Fang  4 ,  Qiaoling Jiang  1  2  3 ,  Ziyan Zhuang  1  2  3 ,  Songzhan Gao  5 ,  Hui Jiang  6  7  8 ,  Qiang Liu  9 ,  Jingtao Guo  1  2  3 ,  Zhe Zhang  4 ,  Xiaoyan Wang  1  2
Affiliations
  • 1. State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
  • 2. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.
  • 3. University of Chinese Academy of Sciences, Beijing, China.
  • 4. Department of Urology, Center for Reproductive Medicine, State Key Laboratory of Female Fertility Promotion, Peking University Third Hospital, Beijing, China.
  • 5. Department of Andrology, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 6. Department of Urology, Peking University First Hospital, Beijing, China.
  • 7. The Institution of Urology, Peking University, Beijing, China.
  • 8. Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, Beijing, China.
  • 9. State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
PMID: 41643060 DOI: 10.1002/advs.202520114
Abstract

The testicular interstitium relies on coordinated signaling among vascular, steroidogenic, and structural cells, yet the regulatory role of testicular endothelial cells (TECs) in maintaining this homeostasis remains unclear. Here, we identify TECs as a central signaling hub that orchestrates intercellular communication within the human testis. Integrative single-cell transcriptomic analysis of healthy and diabetic testes reveals that diabetes disrupts platelet-derived growth factor (PDGF) signaling. TECs in diabetes undergo endothelial-to-mesenchymal transition and exhibit reduced PDGFB expression, while Leydig and testicular peritubular cells downregulate PDGFRB, collectively weakening intercellular connectivity. This disruption silences the JUND-MCL1 survival program in Leydig cells, leading to Apoptosis, extracellular matrix accumulation, and testosterone insufficiency, while impairing the contractility of testicular peritubular cells. Importantly, exogenous PDGF-BB supplementation reactivates the JUND-MCL1 axis, protects Leydig cells, alleviates fibrosis, and partially restores testosterone production and peritubular function. Together, these findings establish endothelial PDGF dysregulation as a key driver of diabetic testicular pathology and highlight PDGF-BB supplementation as a mechanistically grounded therapeutic strategy to restore interstitial and endocrine function in the context of diabetes.

Keywords
JUND; PDGF signaling; leydig cells; single‐cell RNA‐seq; testicular endothelial cells.
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