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Creation and Transplantation of an Adipose-derived Stem Cell ASC Sheet in a Diabetic Wound-healing Model
Published on: August 4, 2017
FGF21-engineered ADSCs promote diabetic wound healing by mitigating ferroptosis and oxidative stress via the
Zhen Liang1, Yanan Gu1, Yutao Li1
1Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
Background:
ADSCs and growth factor-based therapies are widely investigated for diabetic wound healing. However, the clinical translation of ADSCs is limited by their biological instability under hyperglycemic conditions, while exogenous growth factors face challenges such as short half-life and high production costs. Here, we propose a novel strategy using FGF21-engineered ADSCs (ADSCFGF21), leveraging the dual advantages of stem cell paracrine effects and FGF21's established role in metabolic regulation, to target ferroptosis and oxidative stress, key pathological drivers of delayed wound healing in diabetes.
Methods:
To investigate ferroptosis in diabetic wounds, we quantified iron accumulation, DNA oxidative damage (8-OHdG), and lipid peroxidation (MDA assay) in diabetic wound tissues. In vitro, high glucose (HG) treated HUVEC, a model for endothelial dysfunction, were subjected to 7-AAD staining, BODIPY C11-based lipid peroxidation assays, and transmission electron microscopy (TEM) to assess ferroptosis hallmarks. The therapeutic effects of ADSCFGF21 were evaluated through CCK-8 proliferation assays, scratch wound healing, and Matrigel-based tube formation assays under HG conditions. Mechanistic studies involved flow cytometry for ferroptosis distinction, qPCR/Western blot for SIRT1/NRF2/GPX4, AMPK pathway analysis, and immunofluorescence to track NF-κB p65 nuclear translocation.
Results:
We demonstrated that hyperglycemia induces mitochondrial damage, lipid peroxidation, and ferroptosis in diabetic wounds and HG-treated HUVEC. By establishing FGF21-overexpressing ADSCs (ADSCFGF21), we observed enhanced secretion of FGF21, which significantly attenuated HG-induced oxidative stress and restored endothelial cell viability. ADSCFGF21 promoted angiogenesis and accelerated scratch closure. Mechanistically, ADSCFGF21 upregulated NAD+ levels, activating the SIRT1/NRF2 axis, which subsequently enhanced GPX4 expression and suppressed lipid peroxidation. Importantly, AMPK phosphorylation was required for SIRT1/NRF2 axis activation and NF-κB p65 nuclear translocation was inhibited. In diabetic mice, ADSCFGF21 transplantation accelerated wound closure and improved blood perfusion.
Conclusions:
Our study establishes ADSCFGF21 as a multimodal therapy for diabetic wounds, synergizing stem cell-mediated tissue repair with FGF21's metabolic regulation. By activating the SIRT1/NRF2/GPX4 axis, ADSCFGF21 restores redox homeostasis and blocks ferroptosis. These findings provide a promising strategy for chronic wound management.
Insights
Engineered adipose-derived stem cells (ADSCs) secreting FGF21 effectively treat diabetic wounds by reducing ferroptosis and oxidative stress. This novel therapy enhances angiogenesis and accelerates healing through the SIRT1/NRF2/GPX4 pathway.
Area of Science:
- Biomedical Engineering
- Regenerative Medicine
- Cell Therapy
Background:
- Diabetic wound healing is hindered by adipose-derived stem cell (ADSC) instability in hyperglycemia and limitations of growth factor therapies.
- Ferroptosis and oxidative stress are key pathological drivers of delayed wound healing in diabetes.
Purpose of the Study:
- To develop FGF21-engineered ADSCs (ADSCFGF21) for enhanced diabetic wound healing.
- To investigate the mechanisms by which ADSCFGF21 combat ferroptosis and oxidative stress.
Main Methods:
- Quantified ferroptosis markers (iron, 8-OHdG, MDA) in diabetic wounds and high glucose (HG)-treated HUVEC.
- Assessed ADSCFGF21 therapeutic effects on endothelial cell viability, angiogenesis, and wound closure in vitro and in vivo.
- Analyzed molecular pathways including SIRT1/NRF2/GPX4, AMPK, and NF-κB.
Main Results:
- Hyperglycemia induces ferroptosis and oxidative damage in diabetic wound models.
- ADSCFGF21 attenuated HG-induced oxidative stress, restored endothelial cell viability, and promoted angiogenesis.
- ADSCFGF21 activated the SIRT1/NRF2/GPX4 axis, suppressed lipid peroxidation, and inhibited NF-κB signaling, accelerating wound closure in diabetic mice.
Conclusions:
- ADSCFGF21 offers a multimodal therapeutic strategy for diabetic wounds by combining stem cell repair with FGF21 metabolic regulation.
- This approach restores redox homeostasis and blocks ferroptosis, presenting a promising avenue for chronic wound management.
