## 6 Immunomodulatory Capability of MSCs and the Role of MSC Preconditioning  
The MSC is a type of adult stem cell with immunosuppressive and anti-inflammatory properties [96]. It can be used in cell therapy due to its differentiation potential and low immunogenicity [97]. MSCs can differentiate into various specialized cell types, including adipocytes, chondrocytes, osteoblasts, endothelial cells, and cardiomyocytes [98]. The immunomodulatory properties of MSCs are due to their effects on the cytokine profile of lymphocytes [99]. They also inhibit the activity of certain immune cell types such as neutrophils, DCs, anti-inflammatory macrophages, natural killer (NK) cells, and T and B cells, contributing to an overall immunosuppressive environment [100]. The immunomodulatory effects of MSCs are achieved through the paracrine production of various growth factors, cytokines, and mediators of angiogenesis that enable them to modulate immune responses both directly and indirectly. The secretion of IL-8, IL-6, and granulocyte colony-stimulating factor (GM-CSF) by MSCs enhances neutrophil migration to the infection or injury, thereby increasing their activation and phagocytic capacity, as well as promoting their survival. Additionally, MSCs produce a number of important molecules such as transforming growth factor-beta (TGF-\(\beta\)), hepatocyte growth factor (HGF), prostaglandin E2 (PGE2), soluble human leukocyte antigen-G5 (HLA-G5) protein, indoleamine-2,3-dioxygenase (IDO), induced nitric oxide synthase (iNOS), and IL-10, IL-4, and IL-2 to influence the proliferation, differentiation, maturation, and functional activity of various immune cell types, such as T cells, B cells, DCs, macrophages, or NK cells. Furthermore, MSCs do not express MHC II, CD40, CD80, and CD86 molecules, which play a role in T-cell activation during graft rejection [101]. MSCs express intercellular adhesion molecule-1 (ICAM-1), which can interact with lymphocyte function-associated antigen-1 (LFA-1) on T cells and NK cells, thereby reducing their cytotoxicity and proliferation [102; 103]. MSCs can express non-classical human leukocyte antigen-G (HLA-G), a molecule that plays a role in immunological tolerance. HLA-G expression by MSCs can inhibit the cytotoxic activity of NK cells and cytotoxic T cells and increase the expansion of regulatory T cells (Tregs) [104]. One of the main mechanisms by which human MSCs exert immunosuppressive effects is the production of IDO, which is involved in the degradation of L-tryptophan, leading to its depletion and the accumulation of kynure. This in turn inhibits the activation, proliferation, and functional activity of T cells, DCs, NK cells, and Th17 cells' differentiation. Inflammatory diseases stimulate MSC activation via the action of certain cytokines such as IFN-\(\gamma\), TNF-\(\alpha\), IL-17, and IL-1\(\beta\). This activation leads to increased expression of MHC class I/II molecules and costtimulatory molecules. It also increases the proliferation and survival of these cells and their immunomodulatory and immunosuppressive functions [105]. Therapeutic and immunomodulatory effects of cytokines, growth factors, enzymes, and other molecules are partially derived from the activity of MSCs and partially from their interaction with the inflammatory environment. MSCs can produce various cytokines, including TGF-\(\beta\), HGF, and PGE2, especially in response to inflammatory stimuli such as interferon-gamma (IFN-\(\gamma\)) and TNF-\(\alpha\). Additionally, other cytokines like IL-6, IL-10, and IL-1\(\beta\) are often found in the environment where MSCs are active, and their production can be further enhanced through the crosstalk between MSCs and immune cells. This dynamic interaction between MSCs and the inflammatory microenvironment ensures a coordinatedproduction of these molecules, which contribute to the modulation of immune responses and tissue repair processes [106].