# The Application of Mesenchymal Stem Cells on Wound Repair and Regeneration
## 8 Mesenchymal Stem Cells
### Skin Stem Cells  
The skin is the largest organ in the human body, being a protective barrier between the external and internal environment [15]. This organ exhibits enormous regenerative potential since it possesses different stem cell types, responsible for maintaining homeostasis and regulating skin damage. These cells are present in different compartments of the skin; in the epidermis there are three stem cell populations (interfollicular, sebaceous glands and bulge area) which are responsible for the superficial layer homeostasis. Since epidermal stem cells (EPSCs) are a multipotent type of stem cell, they are fundamental to the differentiation and formation of the functional epidermis. The dermis possesses stem cells from the dermal papilla of hair follicles and a population of perivascular stem cells [7; 58]. However, among these different populations of stem cells, EPSCs are of particular interest because of their accessibility and abundance. Keratinocytes are the most relevant cells that belong to the EPSCs population. In addition, these cells are easy to obtain which means there are no ethical issues concerning their use [28]. It is important to note that an efficacious treatment to increase skin regeneration and wound healing would be the stimulation of these cell populations. For example, in full-thickness wounds (damage extends into subcutaneous tissue or even beyond, muscle and bone) cells from hair follicles migrate to the wound site, which means these cells contribute to wound healing. [PERSON] et al. validates this fact by demonstrating a delay in early stages of wound healing in mutant mice which did not possess hair follicles [22; 59]. Epidermal Stem Cells in Cutaneous Wound Healing  
As previously mentioned, wound healing is truly important to repair skin defects and to achieve tensile strength and barrier function. However, serious damage that exceeds the  
Figure 3: Umbilical cord mesenchymal stem cells (MSCs) from three different species (Magnification \(10\times-\) Scale bar = 400 \(\mu\)m): canine (P4), equine (P4) and human (P3). skin regenerative capacity threatens the organism and an effective treatment is required. Concerning wound treatment, it should be long-lasting and depends upon specific medical skills, which constitutes a major challenge. That is the reason why EPSCs are considered a promising choice since they are simple to isolate, accessible and possess skin regenerative capacity [58]. Skin grafts (autografts and allografts) have an important role in wound healing, but face some limitations such as the donor site, immune rejection, infection and scarring. In situations like extensive burns, less skin is available for grafts, so skin substitutes are a promising choice, such as Nile Tilapia fish skin (NTFS) [28; 60]. The commercial skin substitutes consist of a matrix with or without cells that replaces the skin and mimics its functions, which has some limitations like the lack of appropriate mechanical properties. However, the failure of these substitutes is associated with low content of EPSCs, which means that the enrichment with these cells can form an ideal self-renewing epidermis [28; 58]. Concerning nerve regeneration, one of the most usual peripheral nerve injuries results from transactions, which usually happens because of skin penetrating trauma, compression and over-stretching. There are a few therapeutic options and grafts that can be a viable option (autologous grafts and allografts) [61]. The therapeutic strategies most used are the skin substitutes and cultured epidermal autografts (CEAs), which are derived from unpurified cell cultures from the epidermis (containing EPSCs). However, since chronic wounds have a complicated pathogenesis, sometimes many grafts and skin substitutes do not work as expected. The negative cycle of excessive inflammation and dysregulation of matrix metalloproteinases can be interrupted with a transplantation of CEAs enriched with EPSCs on a compatible extracellular matrix [58].