# The Application of Mesenchymal Stem Cells on Wound Repair and Regeneration
## 3 Mechanisms of Injury and Healing  
Skin injury occurs due to direct exposure to potentially harmful mechanical, thermal, chemical or microbial action. The most important cells in regeneration are the tissue-resident stem cells, that have the capability of self-renewing, as well as to differentiate in more specialized cell types and achieve homeostasis. Therefore, when the local and systemic environments change completely, these stem cells exhibit notable plasticity [13; 15]. The adult skin has two different ways of responding to wounds: regeneration or repair. Wound regeneration means that the tissue is capable of replacing the damaged cells for new, fully functioning normal cells, with no scar formation. On the other hand, wound repair refers to the inability to produce normal cells, and therefore fibrotic tissue is produced and consequently a scar is observed [16; 17]. As a result, immediately after an injury, hemostasis occurs, which is followed by other processes such as vasoconstriction, coagulation pathway activation, thrombosis and release of cytokines. Therefore, a wound, depending on the extent of the injury, can heal in one/two weeks naturally, in healthy skin [12; 18; 19; 20]. The epidermis in mammals consists in a stratified squamous epithelium that is maintained by the consecutive proliferation and differentiation of cells from the basal layer. As cells differentiate, they give rise to suprabasal cells, granular layer cells and enucleated corneocytes [21]. Being the most exposed layer of the skin, the epidermis suffers constant injuries and needs to rapidly re-epithelialize to close the lesion site. Furthermore, the epithelial cells and the fibroblasts in the dermis have to migrate and proliferate. In case the wound is not successfully closed, dehydration, inflammation and, in more severe cases, death can occur [21]. When a lesion occurs, fibroblasts and macrophages respond by releasing growth factors that promote fibroblast migration and further proliferation, as well as inflammatory cytokines that induce an immune response. Also, fibroblasts are responsible for the production of collagen and extracellular matrix (ECM) proteins that contribute to fibrosis and scar formation [21]. In the wound site, the accumulation of macrophages and immune cells occurs with the purpose of eliminating microorganisms and to produce growth factors to aid in fibroblast repopulation, re-epithelialization and ECM remodeling [21]. The wound suffers different stages until the skin barrier is stable again, otherwise a disturbance in the normal process of wound healing can advance to the development of a chronic wound [22]. A chronic wound is characterized as loss of skin or other tissues that were not able to heal throughout the normal time that is required. In addition, the treatment of these wounds can be long-lasting and create a huge challenge for contemporary medicine [23; 24]. Therefore, there is a huge necessity to develop different methods that can target the complex biology of chronic-wounds. Some new approaches based on using biomaterials, biologics and cell-based therapies are emerging, and knowing the importance of abnormal inflammation, some studies are focusing on the importance of the immunomodulatory therapies [25; 26]. The enhancing of wound healing using active agents-incorporated bioactive wound-dressings, as well as skin equivalents to repair and regenerate specific skin compartments, are also being explored [26]. The wound delay can be provoked by a number of factors, such as renal disease, diabetes, trauma, advanced age and obesity [15; 22]. Moreover, other local factors like infection, exudates, hypoxia and ischemia can impact in the healing process. Therefore, stem cells have a therapeutic application in cases where the wound-healing process is compromised. Besides, mesenchymal stem cells (MSC)-induced vascular endothelial growth factor (VEGF) production can also promote skin regeneration [27].