## 3 Mesenchymal Stem-Cells in Wound Healing  
MSC are multipotent nonhematopoietic adult stem cells. In the last few years, they have acquired a lot of interest, due to their application in regenerative medicine. MSC can be isolated from various tissues such as umbilical cord blood, endometrium, bone marrow, fat tissues, [PERSON]'s jelly, liver, amniotic fluid, placenta and dental pulp, among others [38]. Furthermore, they are characterized as plastic adherent cells, expressing the surface markers CD73, CD90 and CD105; not expressing CD14, CD34, CD45 and HLA-DR. Surprisingly, MSC have the possibility to differentiate into a wide variety of cells from mesenchymal (osteoblasts, chondrocytes, adipocytes, endothelial cells and cardiomyocytes), and non-mesenchymal (neurons, glial cells and hepatocytes) cell lineages [38; 39; 40]. They are known for their immunosuppressive, anti-inflammatory, tissue restoring, neuroprotection and differentiation properties [40].  
These properties have made them an attractive therapeutic tool in cellular therapy and regenerative medicine. In fact, multiple clinical studies have been published about their applications to different diseases. They include a variety of tumors, multiple sclerosis, amyotrophic lateral sclerosis, acute and chronic heart failure, stroke, [PERSON]'s disease, kidney and liver chronic disease, diabetes, osteoarthritis and rheumatoid arthritis, osteonecrosis, lumbar intervertebral disc degeneration, spinal cord contusions, sepsis, and critical limb ischemia [41]. MSC provide significant therapeutic potential, since they can expand in vitro, can be cryopreserved while maintaining their effectivity, express intermediate and low levels of the MHC class I and II molecules, and can be intravenously administered [17; 39].  
When an injury occurs, MSC are involved in the four wound-healing stages. They can reach the damaged tissue engraftting, differentiating into the convenient cells, as well as triggering anti-inflammatory responses, and promoting neovascularization for tissue regeneration [42]. However, this repair is not only due to MSC, but also to the trophic factors that they secrete, playing a paracrine effect. That is known as secretome and is composed of cytokines, growth factors, chemokines, inflammatory mediators, extracellular-matrix components, proteins and extracellular vesicles, which can mediate cell-to-cell communication, cell differentiation, chemoattraction, immunomododulation, inhibition of fibrosis and apoptosis, as well as secretion of pro-angiogenic factors [38; 43].  
In the case of a skin wound, the physiological response of MSC is the following: TNF-\(\alpha\) and IL-1\(\beta\) are secreted by neutrophils, and MSC infiltrates the wound responding to the local inflammation. When MSC reach the wound, they produce pro-inflammatory cytokines like CCL2, CCL3, CSF2, IL-6 and IL-8, CCL2 and CCL3, recruiting neutrophils and macrophages. These are responsible for activating the adaptive immune system, and begin to degrade damaged tissue. Furthermore, MSC recruit plasmacytoid dendritic cells and limit the number of activated T cells, as well as other innate immune cells, to mediate the transition to the next phase. In the proliferation stage, MSC secrete some proteins and factors, promoting angiogenesis and re-epithelialization (EGF, HGF, VEGF, ANGPT1, PDGF-B and FGF). Also, they can promote resident macrophages to change from inflammatory (M1) toward wound healing (M2) phenotype. Finally, in the remodeling phase, MSC secrete matrix metalloproteinases, inducing matrix deposition and tissue inhibitors of metalloproteinases. That way, they avoid the deposition of extracellular matrix proteins, thus preventing the generation of scars [43].