2. Academic Validation
  3. Regulated cell death environments drive fibroinflammatory reprogramming in surviving adipose-derived stem cells

Regulated cell death environments drive fibroinflammatory reprogramming in surviving adipose-derived stem cells

  • Apoptosis. 2025 Sep 30. doi: 10.1007/s10495-025-02191-0.
Wilfredo Oliva-Olivera 1 2,  Tina Ravnsborg 3,  Elisa Le Boiteux 3,  Eduardo García-Fuentes 4 5,  Lourdes Garrido-Sánchez 6 7 8,  Ole N Jensen 3,  Francisco J Tinahones 9 10 11 12
Affiliations

Affiliations

  • 1 Biomedical Research Institute of Málaga and Nanotechnology Platform - IBIMA BIONAND Platform, 29590, Málaga, Spain. wolivaolivera@ibima.eu.
  • 2 CIBER of Physiopathology of Obesity and Nutrition (CIBERobn), Carlos III Health Institute, 28029, Madrid, Spain. wolivaolivera@ibima.eu.
  • 3 Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230, Odense, Denmark.
  • 4 Clinical Management Unit of Digestive System, Virgen de la Victoria University Hospital, 29010, Málaga, Spain.
  • 5 CIBER of Liver and Digestive Diseases (CIBERehd), Carlos III Health Institute, 28029, Madrid, Spain.
  • 6 Biomedical Research Institute of Málaga and Nanotechnology Platform - IBIMA BIONAND Platform, 29590, Málaga, Spain. lourgarrido@gmail.com.
  • 7 CIBER of Physiopathology of Obesity and Nutrition (CIBERobn), Carlos III Health Institute, 28029, Madrid, Spain. lourgarrido@gmail.com.
  • 8 Clinical Management Unit of Endocrinology and Nutrition, Virgen de La Victoria University Hospital, 29010, Málaga, Spain. lourgarrido@gmail.com.
  • 9 Biomedical Research Institute of Málaga and Nanotechnology Platform - IBIMA BIONAND Platform, 29590, Málaga, Spain.
  • 10 CIBER of Physiopathology of Obesity and Nutrition (CIBERobn), Carlos III Health Institute, 28029, Madrid, Spain.
  • 11 Clinical Management Unit of Endocrinology and Nutrition, Virgen de La Victoria University Hospital, 29010, Málaga, Spain.
  • 12 Department of Medicine and Dermatology, Faculty of Medicine, University of Málaga, 29010, Málaga, Spain.
PMID: 41028407 DOI: 10.1007/s10495-025-02191-0
Abstract

Adipose-derived stem cells (ASCs) can shift toward proinflammatory and fibrotic phenotypes, but factors triggering this transition are not fully understood. This study aimed to elucidate the impact of exposure to regulated cell death environments on the fibroinflammatory potential of surviving subcutaneous ASCs (sub-ASCs). Surviving sub-ASCs were characterized by transcriptional analysis of genes associated with inflammation and extracellular matrix remodeling. Phenotypical markers of fibroinflammatory progenitor cells were monitored by immunoblotting and flow cytometry. We determined post-translational modifications (PTMs) of histone proteins by immunoblotting and mass spectrometry, including individual and combinatorial histone marks. Four days after transient exposure to serum starvation- or tumor necrosis factor-alpha (TNFα)-induced cell death, surviving sub-ASCs cultured under hypoxic proliferative conditions showed elevated mRNA levels of inflammatory mediators, fibrillar collagens, matricellular proteins, and cytoskeletal components. This fibroinflammatory transcriptional activation was accompanied by decreased expression of fibroinflammatory progenitor cell markers. Surviving sub-ASCs exhibited variations in histone methylation marks associated with transcriptional regulation. Inhibiting calcium-dependent μ- and m-calpains during TNFα-induced cell death increased histone marks associated with gene activation and repression, altering surviving sub-ASCs transcriptional responses four days later. Middle-down mass spectrometry identified changes in specific histone MARK combinations in surviving sub-ASCs following TNFα-induced cell death. These findings suggest that regulated cell death environments act as reprogramming agents for surviving ASCs, driving fibro-inflammatory transcriptional activation and histone PTM changes, likely as part of an inducible gene expression program promoting cell survival.

Keywords

Adipose-derived stem cells (ASCs); Fibroinflammatory phenotype; Fibrosis; Histone post-translational modifications (PTMs); Inflammation; Regulated cell death.

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