## 7 Preclinical Studies
### In Vivo Studies  
MSCs and MSC-Exo alleviate psoriasis symptoms through a variety of molecular mechanisms. One key mechanism involves the enhancement of CD4+ T cell activity, which leads to an increased production of IL-4+ and induces apoptosis in cytotoxic T cells. Additionally, MSCs and their exosomes modulate the function of Th1, Th2, Th17, and Treg cells, resulting in elevated levels of IL-10. These actions help maintain an anti-inflammatory environment. The inflammatory environment activates keratinocyte proliferation, which further produces inflammatory cytokines (IL-17A, IL-22) and chemokines (CCL20, CCL27). This positive feedback loop could be halted via the inhibitory action of MSCs and their exosomes. Furthermore, these cells can target dendritic cells, macrophages, and other T cells to curb the production of additional inflammatory factors [133]. At the same time, preclinical studies in animal models (in vivo) have reported new mechanisms of action of MSCs and MSC-Exo that contribute their therapeutic effect in alleviating the symptoms of psoriasis. These mechanisms of action are summarized in Figure 2 and are also described below in the text. [PERSON], et al. found that subcutaneous injection of allogeneic SOD3-transduced MSCs significantly prevented psoriasis development in imiquimod (IMQ)-induced psoriasis-like skin inflammation in mice. They identified that it happens through a suppression of proliferation and infiltration of various effector cells into skin with a concomitant modulated cytokine and chemokine expression and inhibition of signaling pathways such as toll-like receptor-7 (TLR-7), nuclear factor-kappa B (NF-kB), p38 mitogen-activated protein (MAP) kinase, and Janus kinase-signal transducer and activator of transcription (JAK-STAT), as well as adenosine receptor activation [129]. In another study, [PERSON], et al. showed that subcutaneous injection of MSCs prevented and treated IMQ-induced and IL-23-mediated psoriasis-like skin inflammation in a mouse model. The mechanism of action of the MSC is the inhibition of the expression of proinflammatory cytokines (IL-6, IL-17, TNF-\(\alpha\)) and chemokines (CCL17, CCL20, CCL27) [134]. [PERSON], et al. demonstrated that transplantation of tonsil-derived MSCs (T-MSCs) into IMQ-induced psoriasis-like skin inflammation in mice significantly abrogated disease symptoms. This occurs primarily by blunting the Th17 response in a PD-L1-dependent manner, resulting in decreased gene expression of IL-23, TNF-\(\alpha\), IFN-\(\gamma\), IL-17, IL-22, K6, K16, and CCL20 [135]. In a report of [PERSON], et al., in a mouse model of IMQ-induced psoriasis-like skin inflammation MSCs significantly reduced the expression level of proinflammatory cytokines (IL-17, IL-23, IL-6, and IL-1\(\beta\)) and keratinocyte differentiation markers (S100A7, S100A8, and S100A9), and they remarkably increased the expression level of anti-inflammatory cytokine IL-10 [136]. [PERSON], et al. identified that in mice treated with human amnnion-derived MSCs (hAMSC), the gene expression levels of IL-17A, IL-22, and CXCL1 were significantly reduced in the mouse model of IMQ-induced psoriasis [137]. In another study, researchers studied the effect of topical application of MSC-Exo in a mouse model of IMQ-induced psoriasis. They established that MSC-Exo significantly reduce the content of proinflammatory cytokines IL-17 and IL-23 and also terminal complement activation complex C5b-9 in psoriatic skin. According to their suggestion, topical application of MSC-Exo inhibits C5b-9 activation through CD59 in the stratum corneum. Thus, it alleviates IL-17 release by neutrophil extracellular traps (NET\({}_{\text{S}}\)) from neutrophils that accumulate in and beneath the stratum corneum [138]. Figure 2: Mechanisms of action of MSCs and/or MSC-Exo in animal models of psoriasis-like skin inflammation. [PERSON], et al.