4.3. Immunobiology

MSCs are believed to have critical roles in repairing damaged tissues. Tissue injury is associated with the activation of immune/inflammatory cells. In addition, inflammatory mediators, chemokines and leukotrienes, are often produced in the microenvironment by phagocytes in response to damaged cells [32]. Nevertheless, the function of the endothelial cells as a barrier is often broken down in damaged tissues. Thus, these inflammatory molecules and immune cells, together with endothelial cells and fibroblasts, result in the mobilization and differentiation of MSCs and replace the damaged tissue cells. The study of endogenous MSC migration is complex. Once MSCs have entered the microenvironment of injured tissues, MSCs start releasing many growth factors, including epidermal growth factor (tissue regeneration), fibroblast growth factor (cell survival and regeneration), platelet-derived growth factor (tissue repair), vascular endothelial growth factor (angiogenesis and wound healing), hepatocyte growth factor (intrinsic neural cell regeneration), angiopoietin-1 (angiogenesis) and stromal cell-derived factor-1 (neuroprotective effect). These growth factors, in turn, promote the development of fibroblasts, endothelial cells and tissue progenitor cells, which carry out tissue regeneration and repair [33].

### 4.4. Homing

Studies have shown that MSCs have the ability to migrate and to home to a variety of tissues. The migration process is represented by several distinctive steps and starts with the resistance and adhesive interactions between cells flowing through the bloodstream and vascular endothelium. The mechanisms used are assumed to follow the same steps that were described for leukocyte homing.

In the first step, the cells come into contact with the endothelium by tethering and rolling. Different molecules are involved in such process. The selectins on the endothelium are primarily involved and the expression of hematopoietic cell E/L-selectin ligand which is a specialized form of cluster of differentiations (CD), CD44. This step is mediated by the homing receptors expressed on circulating cells which interact with their corresponding receptors expressed on the layer of endothelial cells. [34]. As regards the second step, the cells are activated by G-protein-coupled receptors, followed by integrin-mediated activation. MSCs express various integrins on their surface, among which integrin α4/β1, which mediates cell–cell and cell- extracellular matrix interactions by binding to vascular cell adhesion molecule 1 and to the V-region of fibronectin, respectively. In damaged tissues, fibronectin is deposed together with fibrin at the injured site to stop the bleeding. The provisional matrix is then remodeled by macrophages and fibroblasts, determining an increase in V regionexposing fibronectin, which, in turn, allows MSCs to adhere and transmigrate into the extracellular matrix. In the last step, diapedesis or transmigration occur through the endothelium as well as through the underlying basement membrane. In this step one of the matrix metalloproteinases (MMP) - which are lytic enzymes required to cleave the components of the basement membrane - the gelatinases MMP-2 and MMP-9 are the most important because they specifically degrade collagen and gelatin components of the basement membrane [35].
