## 6 Immunomodulatory Capability of MSCs and the Role of MSC Preconditioning
The therapeutic and immunomodulatory effects of cytokines, growth factors, enzymes, and other molecules produced by MSCs are summarized in Table 2. \begin{table}
\begin{tabular}{p{56.9 pt} p{56.9 pt} p{113.8 pt} p{113.8 pt} p{113.8 pt}} \hline \hline
**Cytokine** & **Type of MSC** & **P preclinical Model** & **Therapeutic and Immunomodulatory Effects** & **Reference** \\ \hline IFN-\(\gamma\) & Bone marrow MSCs (BM-MSCs) & Solid organ transplantation models & IFN-\(\gamma\) primes MSCs to enhance immunosuppressive properties by upregulating IDO and iNOS expression, leading to suppression of T-cell proliferation. & [107] \\  & Human MSCs (hMSCs) & Graft-versus-host disease (GVHD) models & Enhances MSC-mediated immunosuppression and improves outcomes in GVHD by increasing programmed death ligand 1 (PD-L1) expression. Enhances the therapeutic efficacy of MSCs by promoting NO production and reducing apoptosis, thereby improving heart function. & [108] \\  & HNSCs & Inflammatory models in vitro & IL-1\(\beta\) primes MSCs to secrete anti-inflammatory mediators like PGE2, enhancing their immunomodulatory & [110] \\  & Human MSCs (hMSCs) & Cancer immunotherapy models & IL-2 priming enhances MSCs’ ability to inhibit NK cell proliferation and promote Tregs’ differentiation, leading to improved immunosuppression. & [109] \\  & & Autoimmune encephalomyelitis in mice & The combination of IL-17 and TNF-\(\alpha\) significantly enhances the immunosuppressive effects of MSCs, leading to reduced inflammation and better control of autoimmune responses. & [110] \\  & & Cecal ligation and puncture (CLP)-induced sepsis in mice & Attenuation of histopathological damage to the organ, reduction in the level of proinflammatory cytokines, and inhibition of macrophage infiltration into tissues. & [113] \\  & BM-MSCs & Bone metabolism and tissue regeneration & Promotes osteoblast differentiation, bone remodeling, and tissue regeneration. & [114] \\ HGF & BM-MSCs & Spinal cord injury in rats & Promotes recovery by reducing inflammation and enhancing nerve regeneration. & [115] \\  & Gene-modified MSCs & Ischemia/reperfusion-induced acute lung injury in rats & Reduction in lung injury, and improvement of cell survival and tissue repair through anti-apoptotic effect. & [116] \\ PGE2 & BM-MSCs & LPS-induced acute lung injury (ALI) in mice & Enhancement of the protective effects of MSCs by modulating macrophage polarization, reducing inflammation, and improving lung function. & [117] \\  & Human-embryonic-stem-cell-derived MSCs & Liver fibrosis in mouse models & Reduces liver fibrosis through immunosuppressive mechanisms and regulation of T-cell function. & [118] \\ IDO & BM-MSCs & Heart allograft rejection in rats & Suppresses heart allograft rejection by increasing the production and activity of DCs and Tregs. Enhances cardiac function and survival by upregulating IDO expression, which modulates immune response and reduces inflammation. & [119] \\  & hUC-MSCs & Dilated cardiomyopathy (DCM) in rats & Supregulating IDO expression, which modulates immune response and reduces inflammation. & [120] \\ iNOS & BM-MSCs & Systemic sclerosis (SSC) in mice & iNOS activity is crucial for the anti-fibrotic effects of MSCs, reducing skin thickness and collagen deposition. & [121] \\  & hMSCs & Myocardial infarction in rats & Enhances survival and paracrine function of MSCs, leading to reduced apoptosis and improved heart function. & [109] \\ \hline \hline \end{tabular}
\end{table} 
Table 2: Therapeutic and immunomodulatory effects of cytokines, growth factors, enzymes, and other molecules produced by MSCs. Preconditioning with IFN-\(\gamma\) or TNF-\(\alpha\) can increase IDO synthesis in MSCs. Subsequently, this promotes the differentiation of monocytes into IL-10-secreting M2 macrophages. These M2 macrophages exert immunosuppressive effects. Pretreatment of MSCs with IL-17 inhibits the secretion of T helper 1 (Th1) cell cytokines (TNF-\(\alpha\), IFN-\(\gamma\), and IL-2) by T cells and also promotes the activation of Tregs [108].