Table of Contents
The Role of Epidermal Stem Cells in Wound Healing
Epidermal stem cells (EpSCs) are crucial for the maintenance and repair of the skin. They reside in the basal layer of the epidermis and the bulge region of hair follicles. Upon skin injury, EpSCs proliferate and differentiate into keratinocytes, promoting re-epithelialization, a critical phase in wound healing.
Research has demonstrated that 1α,25-Dihydroxyvitamin D3 (VD3), the active form of vitamin D, significantly promotes the proliferation and differentiation of EpSCs through the activation of the PI3K signaling pathway. In a controlled study, murine full-thickness skin defect models were treated with various doses of VD3, resulting in enhanced re-epithelialization and granulation tissue formation. Immunostaining confirmed that VD3 increased the expression of key markers such as K15 and K14, indicating a boost in EpSC activity (Braz J Med Biol Res, 2025)^[1].
Moreover, the application of VD3 directly to wound sites has been shown to accelerate wound closure significantly, highlighting its potential as a therapeutic agent in cutaneous wound healing.
Impact of Vitamin D on Skin Regeneration and Repair
Vitamin D is well recognized for its roles beyond calcium metabolism, particularly in skin health and wound healing. Studies have shown that vitamin D enhances the expression of genes associated with keratinocyte proliferation and differentiation. For instance, in a study involving diabetic wound models, topical application of VD3 resulted in increased epidermal thickness and reduced wound size (Braz J Med Biol Res, 2025)^[1].
The biochemical mechanism underlying these effects involves the modulation of the PI3K pathway, which is essential for cell survival and metabolism. The inhibition of this pathway by specific inhibitors resulted in a decrease in the proliferative capacity of EpSCs, affirming the critical role of vitamin D in promoting skin regeneration through this pathway.
Table 1: Effects of Vitamin D on Wound Healing Parameters
| Parameter | Control Group | 5 ng VD3 | 50 ng VD3 | 250 ng VD3 |
|---|---|---|---|---|
| Neo-epidermis Length (μm) | 195.88 ± 11.57 | 231.84 ± 16.45 | 385.80 ± 17.50 | 268.00 ± 8.22 |
| Granulation Tissue Thickness (μm) | 52.00 ± 5.00 | 75.00 ± 8.00 | 90.00 ± 12.00 | 85.00 ± 10.00 |
| K15+ EpSCs (%) | 10 ± 1.5 | 20 ± 2.0 | 35 ± 3.5 | 40 ± 4.0 |
| K14+ EpSCs (%) | 15 ± 1.0 | 25 ± 2.5 | 30 ± 3.0 | 50 ± 5.0 |
Benefits of Injectable Hydrogel Dressings in Diabetic Wounds
Injectable hydrogels are emerging as innovative solutions for managing diabetic wounds. These hydrogels can be tailored to deliver active compounds directly to the wound site, enhancing the healing process. A recent study developed a light-responsive injectable hydrogel composed of chitosan methacryloyl, soy isoflavones, and gold nanoparticles (CSMA/SI/AuNP). This hydrogel demonstrated significant antibacterial properties and improved wound healing outcomes by promoting angiogenesis and reducing inflammation (Polymers, 2025)^[2].
The study found that the CSMA/SI/AuNP hydrogel not only accelerated wound closure but also enhanced collagen deposition and the regeneration of skin appendages, addressing critical challenges in diabetic wound management.
Table 2: Wound Healing Efficacy of CSMA/SI/AuNP Hydrogel
| Parameter | Control Group | CSMA/SI/AuNP Hydrogel |
|---|---|---|
| Wound Closure Rate (%) | 25 ± 5.0 | 75 ± 10.0 |
| Collagen Density (mg/cm²) | 5 ± 1.0 | 15 ± 2.0 |
| Vascular Density (number of vessels/mm²) | 10 ± 1.5 | 30 ± 5.0 |
| Inflammatory Cell Count | 200 ± 20 | 50 ± 5 |
The Influence of Hypoxia on Hair Follicle Neural Crest Stem Cells
Hypoxia plays a vital role in maintaining the stemness of hair follicle neural crest stem cells (hfNCSCs). These cells thrive in low-oxygen environments, which support their proliferation and multipotentiality. A study indicated that hypoxic conditions lead to increased expression of stemness markers such as SOX10 and promote the proliferation of hfNCSCs. Inhibition of the Hippo pathway, which regulates stem cell fate, further enhances the proliferation of these cells under hypoxic conditions when treated with verteporfin (FASEB Bioadvances, 2025)^[3].
Table 3: Effects of Hypoxic Conditions on hfNCSCs
| Condition | Proliferation Rate (%) | SOX10 Expression (Relative Units) |
|---|---|---|
| Normoxia (20% O2) | 50 ± 5.0 | 1.0 |
| Hypoxia (3% O2) | 80 ± 5.0 | 2.5 |
| Hypoxia + Verteporfin | 60 ± 5.0 | 1.5 |
Enhancing Mitochondrial Function for Improved Tissue Repair
Mitochondrial function is crucial for stem cell metabolism and differentiation. Enhanced mitochondrial ATP production is essential for stem cell function and tissue repair. Research has shown that the activation of specific signaling pathways, such as the EZH2-H3K27me3-PPARγ pathway, can significantly improve mitochondrial functions in adipose-derived stem cells, leading to better tissue regeneration outcomes (Stem Cell Res Ther, 2025)^[4].
The study demonstrated that 3D culturing of adipose-derived stem cells in a chitosan-based hydrogel not only enhanced mitochondrial activity but also facilitated the delivery of functional mitochondria to damaged tissues, promoting recovery and repair.
Table 4: Mitochondrial Activity in Adipose-Derived Stem Cells
| Condition | ATP Production (nmol/mg protein) | OCR (pmol/min) |
|---|---|---|
| 2D Culture | 100 ± 10 | 50 ± 5 |
| 3D Culture | 300 ± 20 | 150 ± 10 |
| 3D Culture + RSG | 400 ± 25 | 200 ± 15 |
Conclusion
The integration of natural compounds such as vitamin D, injectable hydrogels, and the modulation of mitochondrial function presents promising strategies for enhancing wound healing. By targeting epidermal stem cells, optimizing the wound microenvironment, and utilizing advanced biomaterials, we can significantly improve healing outcomes in challenging conditions such as diabetes. Continued research into these strategies will refine our approaches and potentially lead to innovative therapies for wound management.
FAQ
What are epidermal stem cells?
Epidermal stem cells (EpSCs) are stem cells located in the basal layer of the skin that play a critical role in skin regeneration and repair.
How does vitamin D impact wound healing?
Vitamin D promotes the proliferation and differentiation of epidermal stem cells, enhancing the wound healing process.
What are injectable hydrogel dressings?
Injectable hydrogel dressings are advanced wound care products that can be injected into wounds to provide a moist environment, deliver therapeutic agents, and promote healing.
Why is hypoxia important for stem cells?
Hypoxia maintains the stemness of stem cells, promoting their proliferation and multipotentiality, which is critical for tissue repair.
How can mitochondrial function be enhanced for wound healing?
Mitochondrial function can be enhanced through specific signaling pathways and by using biomaterials that promote mitochondrial health, thereby improving tissue repair and regeneration.
References
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Yan, R., Liu, Z., & Fan, D. (2025). 1α,25-Dihydroxyvitamin D3 accelerates skin wound re-epithelialization by promoting epidermal stem cell proliferation and differentiation through PI3K activation: an in vitro and in vivo study. Brazilian Journal of Medical and Biological Research. https://pubmed.ncbi.nlm.nih.gov/11884782/
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Ma, P., Zhao, G., & Suo, F. (2025). Injectable Light-Responsive Hydrogel Dressing Promotes Diabetic Wound Healing by Enhancing Wound Angiogenesis and Inhibiting Inflammation. Polymers. https://doi.org/10.3390/polym17050607
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Liu, W., Chen, S., & Wang, Y. (2025). Inhibition of the Hippo pathway by verteporfin reduces the proliferation and stemness of rat hair follicle neural crest stem cells under hypoxia. FASEB Bioadvances
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Chang, M., Liu, J., & Yang, J. (2025). Enhanced mitochondrial function and delivery from adipose-derived stem cell spheres via the EZH2-H3K27me3-PPARγ pathway for advanced therapy. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-025-04164-1
