*4.1. MSCs in Radiation-Induced Skin Injury*

Radiation-induced skin injury or radiodermatitis is the most common side effect in people exposed to IR. Up to 95% of cancer patients undergoing RT experienced radiodermatitis [54]. Among the manifestation of radiodermatitis, erythema is the most apparent and mild symptom (incidence with more than 90%), followed by moist desquamation (incidence of 30%) [55]. These varying severity levels are associated with direct radiation injuries and consequent inflammations affecting different skin structures, including epidermis, dermis, and vasculature (well described in [56,57]). The release of cytokines and chemokines by recruited immune cells activates dermal fibroblasts, causing chronic dermatitis and skin fibrosis [58]. Regular treatment of radiodermatitis comprises self-care (daily hygiene habits, loose clothing, avoiding tobacco and alcohol, adequate water intake, etc.) and prophylactic topical corticosteroids [59]. Such therapies are usually based on hearsay or physician preferences lacking powered studies to demonstrate their efficiency [60,61]. The occurrence of radiodermatitis has destroyed patients' physical appearance and beauty, and also delayed wound healing [29]. Thus, novel therapeutic validating by a more systematic and rigorous design is urgently needed.

It has demonstrated that bone marrow-derived cells such as MSCs, endothelial progenitors, and myelomonocytic cells are recruited to the injured sites by chemotactic signals SDF-1 and CXCR4 participating in the healing process [62]. The intravenous injection of MSCs significantly accelerates the wound healing rate [63]. Increased survival of BM-MSCs ameliorates injury induced by IR combined with traumatic tissue injury [64]. Thus, scientists have attempted to mitigate radiodermatitis using exogenous administration of MSCs. For instance, Moghaddam et al. intradermally transplanted AT-MSCs (2 <sup>×</sup> <sup>10</sup><sup>6</sup> ) to guinea pigs receiving 60 Gy abdominal radiation. These irradiated guinea pigs showed alleviated skin damage, and the combination of low-intensity ultrasound enhanced the curative effect of AT-MSCs [65]. However, the exact mechanism underlying the therapeutic potential of MSCs for radiodermatitis is unclear. Anti-inflammation and anti-fibrosis may be the main ways for MSCs to inhibit radiation injury [66,67]. Inflammation-related cytokines (IL1β and IL10) were regulated by BM-MSCs (5 <sup>×</sup> <sup>10</sup><sup>5</sup> ) in radiation mice models with a 35 Gy dose [67]. Similarly, BM-MSCs injection (2 <sup>×</sup> <sup>10</sup><sup>6</sup> ) via tail vein efficiently reduced 45 Gy radiation-induced rats' skin fibrosis reflected by decreased TGF-β1 [66]. Notably, the MSCs conditioned medium (CM) could also accelerate wound healing after pipetting onto the irradiated rats' skin wound [68]. This result indicated that paracrine factors from MSCs play a critical role in repairing radiodermatitis by mitigating the injury site's inflammatory microenvironment. Apart from animal studies, limited clinical trials were also carried out. A case report analyzed the treatment potential of cadaveric MSCs on a necrotic ulcer in a patient receiving 50–60 Gy dose RT for right leg angioma [69]. Two years after the treatment, clinicians observed a reduced ulcer size and improved the skin quality, confirming the MSC therapy's efficiency. Thus, MSCs or their secretiome could be novel therapeutics for mitigating the radiodermatitis.
