Among the traditional treatment methods for skin wound repair, skin grafting, biological scaffolds, skin flap surgery, and laser therapy are the most common. Skin grafting is often used for large-area trauma or ulcers. Wound dressings also play a crucial role in skin wound repair, offering properties such as wound protection, reduced secretions, antibacterial effects, maintenance of a moist environment, high breathability, and non-allergenicity. In recent years, numerous domestic and foreign researchers have discovered that mesenchymal stem cells (MSCs), as a type of pluripotent stem cell with self-renewal and multilineage differentiation capabilities, possess advantages such as a wide range of sources, low immunogenicity, and no additional damage to the patient's skin. They have demonstrated considerable therapeutic potential in skin injury repair.

Mesenchymal stem cells (MSCs) refer to a group of stem cells with self-renewal, immunomodulatory, and multipotent differentiation capabilities. They can be broadly classified into two major categories: pluripotent stem cells and adult stem cells. These include human umbilical cord mesenchymal stem cells (hUCMSCs), bone marrow mesenchymal stem cells (BMMSCs), endometrial mesenchymal stem cells (EnMSCs), adipose-derived stem cells (ADSCs), dental-derived mesenchymal stem cells (DMSCs), and induced pluripotent stem cell-derived mesenchymal stem cells (iMSCs). Bone marrow mesenchymal stem cells were the first MSCs to be isolated and are currently the most extensively studied, researched, and applied type of MSC in stem cell therapy. Their efficacy and safety have been confirmed in multiple studies.

The umbilical cord, belonging to extraembryonic tissue, contains a vast number of multipotent stem cells. Umbilical cord mesenchymal stem cells are isolated from various structures such as the entire umbilical cord, Wharton's jelly, amnion, vascular endothelium, and perivascular tissues. Menstrual blood mesenchymal stem cells originate from the sloughed-off endometrium during menstruation in women. Since they can be obtained non-invasively and safely from all women of reproductive age through menstrual blood collection, menstrual blood stem cells hold significant potential for clinical applications.

Dental mesenchymal stem cells are adult stem cells isolated from the lamina propria of gingival tissue. Induced pluripotent stem cells (iPSCs) are generated by reprogramming differentiated adult cells to a pluripotent state, resembling embryonic stem cells in their low differentiation characteristics. Being derived from the patient's own tissues, iPSCs eliminate ethical concerns and can avoid immune rejection and tumorigenicity risks, making them a highly attractive option.

Mechanisms of Mesenchymal Stem Cells in Facilitating Skin Injury Repair

1.Differentiation and Immunomodulation

MSCs possess the capability of specific differentiation within their microenvironment, enabling them to transform into skin cells at sites of injury to participate in the repair process. In animal models of wound healing, transplanted MSCs have been observed to differentiate into resident cells of the local tissue at the wound site, including fibroblasts, myofibroblasts, vascular endothelial cells, pericytes, and keratinocytes. Furthermore, MSCs exhibit immunomodulatory effects. Research has shown that upon stimulation by relevant inflammatory factors, MSCs demonstrate potent immunosuppressive activity. For instance, activated MSCs by inflammatory factors can secrete an anti-inflammatory protein, TSG-6, which inhibits macrophage activation and reduces immune response. Additionally, MSCs can activate M2 macrophages to produce interleukin-10 (IL-10), an anti-inflammatory cytokine with therapeutic effects on wound healing. By inhibiting neutrophil infiltration and T-cell response, IL-10 can suppress inflammatory reactions, indicating that the immunomodulatory capabilities of MSCs can improve chronic, refractory inflammatory wounds and effectively promote wound healing.

2. Paracrine Effects

MSCs within the wound area secrete a variety of growth factors and cytokines, such as vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), angiogenin, interleukin-6 (IL-6), and transforming growth factor-β (TGF-β). These active factors, through the paracrine effects of MSCs, promote angiogenesis and wound healing, thereby improving symptoms associated with complications. Studies have shown that stromal cell-derived factor-1 (SDF-1) secreted by transplanted MSCs and its membrane receptor, CXCR4 chemokine receptor, are involved in the homing and migration of various stem cells, cell proliferation, and angiogenesis. This process can induce the accumulation of endogenous MSCs and endothelial progenitor cells at the wound site, accelerating skin healing.

The paracrine function of MSCs plays a pivotal role in modifying the vascular microenvironment of tissues, enhancing the regenerative capacity of injured tissues, stimulating the proliferation and differentiation of epithelial-like progenitor cells, and mitigating inflammation and immune responses. During the healing process, the paracrine effects of MSCs also contribute to the production and remodeling of the extracellular matrix (ECM). Research has found that MSCs secrete abundant tissue inhibitors of metalloproteinases (TIMPs), which stabilize blood vessels and protect vascular basement membranes from degradation induced by matrix metalloproteinases (MMPs). This process promotes the synthesis of fibronectin, collagen, and elastin by dermal fibroblasts.

3. Exosome Secretion

Exosomes secreted by mesenchymal stem cells (MSCs) serve as crucial vehicles for the biological effects of these stem cells. Exosomes carry a diverse array of active substances from MSCs and, by transferring molecules such as active proteins and nucleic acids to target cells, play a role during the inflammatory response phase, cell proliferation phase, and tissue remodeling phase. They participate in regulating multiple aspects of the wound healing process, including inflammation, cell proliferation and migration, angiogenesis, and matrix reconstruction, thereby promoting wound healing and inhibiting scar formation.

Research has demonstrated that MSCs can promote the polarization of macrophages towards the M2 phenotype, thereby counteracting the inflammatory response induced by skin injury. Specifically, human bone marrow-derived mesenchymal stem cell (hBMSC) exosomes can facilitate the anti-inflammatory M2 polarization of macrophages by activating the PTEN/AKT signaling pathway. This process inhibits the pro-inflammatory M1 polarization and reduces the expression of pro-inflammatory factors such as IL-1β and TNF-α, while enhancing the expression of the anti-inflammatory factor IL-10. Consequently, it accelerates skin wound healing in diabetic mice. In a simulated inflammatory state, the specific expression of miRNA let-7b in human umbilical cord blood-derived mesenchymal stem cell (hUCB-MSC) exosomes regulates macrophage polarization in a stable manner through the TLR4/NF-κB/STAT3/AKT signaling pathway. This promotes the differentiation of macrophages towards the anti-inflammatory M2 phenotype, mitigates the inflammatory response, and enhances wound healing in diabetic skin injuries.

MSCs have been proven to directly enter fibroblasts through internalization pathways, promoting their proliferation, migration, and collagen synthesis, which in turn accelerates wound healing. When adipose-derived mesenchymal stem cell (ADSC) exosomes enter fibroblasts, they stimulate cell proliferation and collagen synthesis by upregulating the expression of N-cadherin, cyclin-1, proliferating cell nuclear antigen, type I collagen, type III collagen, metalloproteinase-1, basic fibroblast growth factor, and transforming growth factor-β1 (TGF-β1). This process accelerates skin wound healing. Furthermore, exosomes can regulate the proliferation and migration of recipient cells by releasing active substances into them. Specifically, lncRNA H19 within human bone marrow-derived mesenchymal stem cell (hBMSC) exosomes interacts with miR-152-3p in fibroblasts, inhibiting the expression of phosphatase and tensin homolog while simultaneously activating the PI3K/AKT signaling pathway. This cascade promotes the proliferation and migration of fibroblasts, inhibits their apoptosis, and enhances wound healing in diabetic mice.

The active proteins or nucleic acids carried within MSC exosomes can modulate the expression of other active factors within endothelial cells, indirectly promoting angiogenesis. For instance, Wnt4 protein present in human umbilical cord blood-derived mesenchymal stem cell (hUCB-MSC) exosomes can enter endothelial cells, inducing β-catenin activation. This, in turn, enhances the expression of PCNA, cyclin-D3, and N-cadherin, thereby promoting angiogenesis. Additionally, adipose-derived mesenchymal stem cell (ADSC) exosomes are rich in miR-125a, which can inhibit the transcription and expression of the angiogenesis inhibitor DLL4. By promoting the formation of endothelial tip cells, miR-125a within ADSC exosomes facilitates the generation of blood vessels from endothelial cells.

Scar formation is the final process of wound healing, characterized primarily by significant proliferation of fibroblasts, excessive deposition of collagen, and synthesis of extracellular matrix, leading to the development of pathological scars. Research has found that following the injection of adipose-derived mesenchymal stem cell (ADSC) exosomes, histological analysis of mouse wounds revealed that during the early stages of wound healing, exosomes increased the production of type I and type III collagen. However, in later stages, exosomes may inhibit collagen expression to reduce scar formation. ADSC exosomes regulate collagen deposition and arrangement by modulating the ratio of type III to type I collagen. They also regulate fibroblast differentiation by adjusting the ratio of TGF-β3 to TGF-β1, which helps to mitigate scar formation. Furthermore, ADSC exosomes can activate the ERK/MAPK pathway, increasing the expression of MMP3 in dermal fibroblasts, leading to an elevated ratio of MMP3 to tissue inhibitor of metalloproteinase-1 (TIMP-1). This process facilitates the remodeling of extracellular matrix and promotes scarless wound repair.

References

[1] Li Man, Zhu Wei, Zhang Haiping. Research Progress on Exosomes Derived from Mesenchymal Stem Cells of Different Origins in Skin Injury Repair [J]. Chinese Journal of Injury and Repair (Electronic Version), 2021, 16(06): 515-519.

[2] Sun Xuan, Mao Nianyu, Liu Mingzhu, Dong Chuanming. Research Progress of Exosomes Derived from Mesenchymal Stem Cells in Skin Injury Repair [J]. Journal of Systemic Medicine, 2019, 4(16): 196-198. DOI: 10.19368/j.cnki.2096-1782.2019.16.196.

[3] Cong Haiyan, Wang Na, Chang Xin, Wang Haitao, Yang Jincun. Research Progress on the Role and Mechanism of Exosomes Derived from Mesenchymal Stem Cells in Promoting Skin Wound Repair [J]. Journal of Shandong First Medical University & Shandong Academy of Medical Sciences, 2022, 43(08): 620-625.

[4] Cheng Yansiwei, Song Guanbin. Mesenchymal Stem Cells and Skin Injury Repair [J]. Journal of Biomedical Engineering, 2021, 38(02): 387-392.

About the Author

Xiaonisha, a food technology professional holding a Master's degree in Food Science, is currently employed at a prominent domestic pharmaceutical research and development company. Her primary focus lies in the development and research of nutritional foods, where she contributes her expertise and passion to create innovative products.