Acteoside-Loaded Self-Healing Hydrogel Enhances Skin Wound Healing through Modulation of Hair Follicle Stem Cells

Medicine Materials Science Life Sciences Bioengineering Cell Biology
skin trauma self-healing hydrogel acteoside Rab31 hair follicle stem cells

Skin wound healing is a complex biological process involving the coordination of cellular, molecular, and physiological events. Although traditional treatment methods can promote wound closure to some extent, their efficacy is often unsatisfactory in chronic wounds or complex trauma environments, particularly in controlling infections and inflammatory responses. In recent years, with the rapid development of the biomedical field, self-healing hydrogels have gradually become a research hotspot for promoting wound healing due to their excellent physicochemical properties and biocompatibility. Additionally, the natural compound acteoside (verbascoside) has shown potential in accelerating wound healing and reducing scar formation due to its antioxidant, anti-inflammatory, and cell proliferation-promoting properties. However, how to effectively deliver acteoside to the wound site and regulate its biological functions remains a challenge in current research.

The core objective of this study is to develop a self-healing hydrogel loaded with acteoside to promote skin wound healing by modulating the function of hair follicle stem cells (HFSCs). The research not only explores the molecular mechanisms of acteoside but also validates its practical application in animal models, providing a new strategy for skin wound treatment.

Source of the Paper

This paper was co-authored by Junyu Liu, Hua Wang, and Caihua Zhang, affiliated with Shandong Ruixin Pharmaceutical Company and Shandong Luoxin Pharmaceutical Group Stock Company, respectively. The paper was accepted on March 18, 2025, and published in the journal Cellular and Molecular Bioengineering, with the DOI 10.1007/s12195-025-00845-2.

Research Process and Results

1. Transcriptome Analysis and Target Gene Screening

The study first downloaded skin trauma-related transcriptome datasets (GSE28914, GSE50425, and GSE23006) from the Gene Expression Omnibus (GEO) database and performed differential gene expression analysis using the limma package. Through functional enrichment analysis, the researchers found that acteoside might influence the skin healing process by regulating the Rab31 gene. Further molecular docking experiments showed that the binding energy between acteoside and Rab31 was the lowest (-9.6 kcal/mol), suggesting that acteoside may function through Rab31.

2. Single-Cell Transcriptome Sequencing and Cell Type Annotation

To verify the specific role of Rab31 in skin wound healing, the researchers analyzed a single-cell transcriptome dataset of mouse skin trauma (GSE186527). Using the Seurat software package for data normalization and clustering analysis, the researchers found that Rab31 was highly expressed in hair follicle stem cells (HFSCs) and fibroblasts. This result suggests that Rab31 may play a key role in the proliferation, migration, and differentiation of HFSCs.

3. Isolation and Functional Validation of HFSCs

The researchers isolated HFSCs from the dorsal skin of mice and identified them through flow cytometry and immunofluorescence staining. In vitro experiments showed that the overexpression of Rab31 significantly promoted the proliferation and migration of HFSCs, while the silencing of Rab31 inhibited these functions. Western blot analysis further confirmed that the regulation of Rab31 affected the expression of differentiation markers (such as α6-integrin and CK10) in HFSCs.

4. Preparation and Characterization of Self-Healing Hydrogel

The researchers developed a self-healing hydrogel based on quaternized chitosan derivatives (QCS) for loading acteoside. Through the formation of dynamic boronate ester bonds, the hydrogel exhibited excellent mechanical properties and self-healing capabilities. Rheological tests showed that the hydrogel exhibited shear-thinning behavior under shear stress and could quickly recover its structure under physiological pH conditions. Additionally, the pH sensitivity of the hydrogel enabled the rapid release of acteoside in acidic environments, making it suitable for the treatment of infected wounds.

5. Evaluation of Antibacterial and Antioxidant Properties of the Hydrogel

In vitro experiments demonstrated that the acteoside-loaded hydrogel exhibited significant antibacterial activity against Escherichia coli and Staphylococcus aureus. Furthermore, the hydrogel showed strong free radical scavenging ability, effectively reducing oxidative stress at the wound site.

6. Validation in Animal Models

In a mouse skin wound model, the acteoside-loaded hydrogel significantly accelerated the wound healing process. Histological analysis showed that the epithelialization rate and collagen deposition in the hydrogel-treated group were significantly higher than those in the control group. RT-qPCR results further confirmed that the hydrogel promoted the proliferation and differentiation of HFSCs by upregulating the expression of Rab31.

Conclusion and Significance

This study successfully developed a self-healing hydrogel loaded with acteoside and significantly promoted the proliferation, migration, and differentiation of hair follicle stem cells by regulating the Rab31 gene, thereby accelerating skin wound healing. The research not only revealed the molecular mechanisms of acteoside but also validated its practical application in animal models, providing a new strategy for skin wound treatment. Additionally, the antibacterial and antioxidant properties of the hydrogel further enhanced its potential application in complex trauma environments.

Research Highlights

  1. Innovation: For the first time, acteoside was combined with a self-healing hydrogel to effectively regulate the function of HFSCs by modulating the Rab31 gene.
  2. Multidimensional Research: Combining transcriptome analysis, single-cell sequencing, and animal models, the study comprehensively revealed the mechanism of action of acteoside.
  3. Application Value: The developed hydrogel exhibits excellent antibacterial, antioxidant, and self-healing properties, making it suitable for the treatment of various skin wounds.

Future Prospects

Although this study achieved significant results in mouse models, its application in human clinical settings requires further validation. Additionally, the specific molecular mechanisms between acteoside and Rab31, as well as the effects of the hydrogel on different types and severities of wounds, need further exploration. Future research will further optimize the performance of the hydrogel and promote its clinical translation, providing more effective solutions for skin wound treatment.