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Peer-reviewedCC BY-NC-ND 4.0Balkan Medical Journal

HUCMSCs-Derived Exosomes Attenuate Keloid Fibroblast Pathological Phenotypes with Associated Metabolic-Redox-Matrix Network Remodeling: A Proteomic and In Vivo Study

  • Zimiao Chen1,2
  • Lina Lu3
  • Qin Liu2
  • Xiaosong Chen1
  1. 1Department of Plastic Surgery and Regenerative Medicine, Fujian Medical University Union Hospital, Fujian, China
  2. 2Department of Medical Aesthetics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Guangdong, China
  3. 3Department of Hematology, Shenzhen Longhua District Central Hospital, Guangdong, China
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Abstract

Background: Human umbilical cord mesenchymal stem cell-derived exosomes (HUCMSCs-Exo) have emerged as investigational cell-free candidates for the treatment of fibrotic diseases.

Aims: To examine the phenotypic effects of HUCMSCs-Exo on keloid fibroblasts (KFs) in vitro, characterize associated proteomic, hub-protein, and redox-mitochondrial changes, and evaluate their in vivo effects using a nude mouse xenograft model.

Study Design: In vitro and in vivo study.

Methods: HUCMSCs-Exo were isolated by differential ultracentrifugation and characterized using transmission electron microscopy, nanoparticle tracking analysis, and Western blotting for CD9, CD63, and CD81. Label-free quantitative proteomics, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and protein-protein interaction (PPI) network analysis were performed. Western blot validation, DCFH-DA, JC-1, and MitoSOX assays, and peritumoral administration of HUCMSCs-Exo in vivo, together with biosafety evaluations based on hematology, serum biochemistry, and organ histopathology, were performed.

Results: PKH67-labeled exosomes were internalized by KFs in a time-dependent manner. In vitro, HUCMSCs-Exo inhibited KF proliferation in a dose- and time-dependent manner, induced apoptosis, caused cell-cycle arrest at the G0/G1 phase, and suppressed migration. The expression of fibrosis-associated markers, including fibronectin (FN1), alpha-smooth muscle actin (α-SMA), collagen type I (COL-I), and collagen type III (COL-III), was downregulated at both the mRNA and protein levels. Label-free quantitative proteomics identified 951 differentially expressed proteins. KEGG enrichment analysis demonstrated enrichment in metabolic pathways, carbon metabolism, and glycolysis/gluconeogenesis. PPI network analysis identified seven candidates hub proteins, of which APEX1, MMP2, and HMOX1 remained significant after Benjamini-Hochberg correction; the other four candidates, including TGFB1, did not survive correction. Therefore, the matrix- and TGF-beta-related findings are supported by orthogonal validation rather than by the corrected proteomic screen alone. Western blot validation demonstrated reduced abundance of TGFB1, MMP2, TIMP1, and TXN2 and increased abundance of APEX1 after HUCMSCs-Exo treatment. The DCFH-DA, JC-1, and MitoSOX assays indicated reduced intracellular reactive oxygen species levels, preservation of mitochondrial membrane potential, and reduced mitochondrial superoxide signals. In vivo, peritumoral administration of HUCMSCs-Exo suppressed keloid xenograft growth and was accompanied by reduced collagen deposition and lower expression of FN1, α-SMA, COL-I, and COL-III. Biosafety evaluation revealed no detectable abnormalities in hematology, serum biochemistry, or organ histopathology under the conditions tested.

Conclusion: The combined data indicate that HUCMSCs-Exo attenuate KF proliferation and fibrogenic phenotypes and are accompanied by proteomic, hub-protein, and redox-mitochondrial changes consistent with metabolic-redox-matrix network remodeling. These molecular associations are correlative and were not tested using perturbation experiments.

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Cite

BibTeXRIS
BibTeX
@article{chen2026hucmscsderived,
  title = {{HUCMSCs-Derived Exosomes Attenuate Keloid Fibroblast Pathological Phenotypes with Associated Metabolic-Redox-Matrix Network Remodeling: A Proteomic and In Vivo Study}},
  author = {Zimiao Chen and Lina Lu and Qin Liu and Xiaosong Chen},
  journal = {Balkan Medical Journal},
  year = {2026},
  month = nov,
  doi = {10.4274/balkanmedj.galenos.2026.2026-5-27},
  url = {https://doi.org/10.4274/balkanmedj.galenos.2026.2026-5-27},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - HUCMSCs-Derived Exosomes Attenuate Keloid Fibroblast Pathological Phenotypes with Associated Metabolic-Redox-Matrix Network Remodeling: A Proteomic and In Vivo Study
AU  - Zimiao Chen
AU  - Lina Lu
AU  - Qin Liu
AU  - Xiaosong Chen
PY  - 2026
DA  - 2026/11/02
JO  - Balkan Medical Journal
DO  - 10.4274/balkanmedj.galenos.2026.2026-5-27
UR  - https://doi.org/10.4274/balkanmedj.galenos.2026.2026-5-27
AB  - Background: Human umbilical cord mesenchymal stem cell-derived exosomes (HUCMSCs-Exo) have emerged as investigational cell-free candidates for the treatment of fibrotic diseases.  Aims: To examine the phenotypic effects of HUCMSCs-Exo on keloid fibroblasts (KFs) in vitro, characterize associated proteomic, hub-protein, and redox-mitochondrial changes, and evaluate their in vivo effects using a nude mouse xenograft model.  Study Design: In vitro and in vivo study.  Methods: HUCMSCs-Exo were isolated by differential ultracentrifugation and characterized using transmission electron microscopy, nanoparticle tracking analysis, and Western blotting for CD9, CD63, and CD81. Label-free quantitative proteomics, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and protein-protein interaction (PPI) network analysis were performed. Western blot validation, DCFH-DA, JC-1, and MitoSOX assays, and peritumoral administration of HUCMSCs-Exo in vivo, together with biosafety evaluations based on hematology, serum biochemistry, and organ histopathology, were performed.  Results: PKH67-labeled exosomes were internalized by KFs in a time-dependent manner. In vitro, HUCMSCs-Exo inhibited KF proliferation in a dose- and time-dependent manner, induced apoptosis, caused cell-cycle arrest at the G0/G1 phase, and suppressed migration. The expression of fibrosis-associated markers, including fibronectin (FN1), alpha-smooth muscle actin (α-SMA), collagen type I (COL-I), and collagen type III (COL-III), was downregulated at both the mRNA and protein levels. Label-free quantitative proteomics identified 951 differentially expressed proteins. KEGG enrichment analysis demonstrated enrichment in metabolic pathways, carbon metabolism, and glycolysis/gluconeogenesis. PPI network analysis identified seven candidates hub proteins, of which APEX1, MMP2, and HMOX1 remained significant after Benjamini-Hochberg correction; the other four candidates, including TGFB1, did not survive correction. Therefore, the matrix- and TGF-beta-related findings are supported by orthogonal validation rather than by the corrected proteomic screen alone. Western blot validation demonstrated reduced abundance of TGFB1, MMP2, TIMP1, and TXN2 and increased abundance of APEX1 after HUCMSCs-Exo treatment. The DCFH-DA, JC-1, and MitoSOX assays indicated reduced intracellular reactive oxygen species levels, preservation of mitochondrial membrane potential, and reduced mitochondrial superoxide signals. In vivo, peritumoral administration of HUCMSCs-Exo suppressed keloid xenograft growth and was accompanied by reduced collagen deposition and lower expression of FN1, α-SMA, COL-I, and COL-III. Biosafety evaluation revealed no detectable abnormalities in hematology, serum biochemistry, or organ histopathology under the conditions tested.  Conclusion: The combined data indicate that HUCMSCs-Exo attenuate KF proliferation and fibrogenic phenotypes and are accompanied by proteomic, hub-protein, and redox-mitochondrial changes consistent with metabolic-redox-matrix network remodeling. These molecular associations are correlative and were not tested using perturbation experiments.
SN  - 2146-3123
SN  - 2146-3131
ER  -