Tunneling nanotube-mediated stem cell immunomodulation dysfunction promotes adipose inflammation and insulin resistance in GDM

  • Cell Rep. 2025 Nov 25;44(11):116505. doi: 10.1016/j.celrep.2025.116505.
Bingnan Chen  1 ,  Xuyang Chen  2 ,  Jianxin Li  2 ,  Ruohan Hu  3 ,  Lijun Yang  2 ,  Hongli Li  2 ,  Xinmi Liu  2 ,  Richard D Cannon  4 ,  Richard Saffery  5 ,  Boris Novakovic  5 ,  Hongbo Qi  2 ,  Hua Zhang  6 ,  Xiaobo Zhou  7
Affiliations
  • 1. Department of Obstetrics and Gynecology, Chongqing Key Laboratory of Maternal and Fetal Medicine / Joint International Research Laboratory of Reproduction & Development, Ministry of Education / The Innovation and Talent Recruitment Base of Maternal-Fetal Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
  • 2. Department of Obstetrics and Gynecology, Chongqing Key Laboratory of Maternal and Fetal Medicine / Joint International Research Laboratory of Reproduction & Development, Ministry of Education / The Innovation and Talent Recruitment Base of Maternal-Fetal Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 3. Biomedical Sciences, University of Otago, Dunedin, New Zealand.
  • 4. Department of Oral Sciences, Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand.
  • 5. Molecular Immunity, Infection and Immunity Theme, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC, Australia.
  • 6. Department of Obstetrics and Gynecology, Chongqing Key Laboratory of Maternal and Fetal Medicine / Joint International Research Laboratory of Reproduction & Development, Ministry of Education / The Innovation and Talent Recruitment Base of Maternal-Fetal Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: [email protected].
  • 7. Department of Obstetrics and Gynecology, Chongqing Key Laboratory of Maternal and Fetal Medicine / Joint International Research Laboratory of Reproduction & Development, Ministry of Education / The Innovation and Talent Recruitment Base of Maternal-Fetal Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: [email protected].
PMID: 41187060 DOI: 10.1016/j.celrep.2025.116505
Abstract

Adipose-derived stem cells (ADSCs) represent a promising therapeutic resource, yet their immunometabolic regulation remains poorly defined. Here, we reveal a tunneling nanotube (TNT)-mediated communication mechanism between ADSCs and adipose tissue macrophages (ATMs) that maintains metabolic homeostasis during pregnancy. Using gestational diabetes mellitus (GDM) mouse models combined with live-cell imaging, scanning electron microscope, and multi-omics approaches, we demonstrate that mitochondrial transfer from ADSCs to ATMs via TNTs sustains ATM metabolic fitness. This process is governed by the WNT5A-RhoA-ROCK1 axis and becomes impaired under metabolic stress, driving ATMs inflammatory polarization and Insulin resistance. Importantly, in situ ADSC administration restores mitochondrial transfer and improves metabolic parameters in GDM mice. Collectively, our work establishes TNT-mediated organelle sharing as a fundamental mechanism of stem cell-immune interaction and demonstrates that ADSC-based therapy represents a promising strategy for GDM by reprogramming the metabolism of immune cells.

Keywords
CP: Metabolism; CP: Stem cell research; adipose tissue macrophages; adipose-derived stem cells; gestational diabetes mellitus; mitochondria; tunneling nanotubes.
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