*4.5. MSCs in Radiation-Induced Hepatic Injury*

Radiation-induced hepatic injury (RIHI) presents two different clinical types (classic and non-classic RIHI) reflected by distinct characteristics [121]. Both of them occurred in 36% of patients receiving reirradiation for hepatocellular carcinoma [122]. Classic RIHI is recognized by hepatomegaly, anicteric ascites, and increased abdominal circumference [123]. Patients with classic RIHI show upregulated alkaline phosphatase but normal transaminase and bilirubin levels [124]. The veno-occlusive disease, an essential manifestation of classic RIHI, is described as a complete blockage of the central vein by erythrocytes attached to a dense network of reticulin and collagen fibers [125]. Non-classic RIHI represents an impaired liver function in those patients with chronic hepatic injury, such as viral hepatitis and cirrhosis. Jaundice or significantly elevated serum transaminases levels (five times higher than the standard value) could be used to confirm non-classic RIHI [126]. Transaminases are an important biomarker for assessing the hepatic injury. After irradiation, human or rat MSCs perfusion significantly reduced serum transaminase activity, indicating recovered liver function [127,128]. The mechanism might be apoptosis inhibition due to decreased ROS production and increased secretion of anti-inflammatory IL-10 [127]. In another study, the combined intravenous administration of BM-MSCs (1 <sup>×</sup> <sup>10</sup><sup>6</sup> ) and nigella sativa oil present a similar protective effect on the liver [128]. In addition to inherent medicinal value, nigella sativa oil could enhance MSCs homing in injured liver sites. However, Moubarak et al. found that intravenous MSCs were not grafted to the liver but to the intestine following abdominal irradiation. Improved intestinal damage indirectly corrects liver abnormality via enterohepatic recirculation [129]. Meanwhile, the paracrine mechanism played a more critical role and dominated the protection of MSCs against RIHI without liver engraftment. With increased recognition of the paracrine effect, MSCs-CM was also used to examine paracrine factors' repair capability to RIHI [130]. In vitro administration of MSCs-CM for culturing sinusoidal endothelial cells increased cell viability and blocked apoptosis. In vivo injection of MSCs-CM into irradiated rat reversed radiation-induced hepatic histopathological changes. Critical nutritional factors responsible for the regeneration potential were unclear, but the mechanism may be related to phosphorylation activation of AKT and ERK. Among all beneficial growth factors secreted from MSCs, hepatocyte growth factor possesses multiple tissue repair abilities, especially liver regeneration. Gene-modified AT-MSCs over-expressing HGF downregulated profibrotic proteins (α-SMA and fibronectin) and showed greater anti-fibrotic potential on the irradiated liver in comparison to unmodified MSCs [131]. Unfortunately, there are still no relevant clinical report to date.
