Abstract
To evaluate the potential therapeutic effect of the infusion of hMSCs for the correction of liver injuries, we performed total body radiation exposure of NOD/SCID mice. After irradiation mir-27b level decreases in liver, increasing the directional migration of hMSCs by up-regulating SDF1α. Significant increases in plasmatic transaminases levels, apoptosis process in the liver vascular system, and oxidative stress were observed. hMSC injection induced a decrease in transaminases levels and oxidative stress, a total disappearance of apoptotic cells, an increase in Nrf2, SOD gene expression, which might ROS production in the injured liver. Engrafted hMSCs expressed cytokeratin CK18, CK19 and AFP genes indicating possible hepatocyte differentiation. The presence of hMSCs expressing VEGF and Ang-1 in the peri-vascular region, associated with an increased expression of VEGFr1, r2 in the liver, can confer a role of secreting cells to MSCs in order to maintain the endothelial function. To explain the benefits for the liver of hMSC engraftment, we find that hMSCs secreted NGF, HGF and anti-inflammatory molecules (IL-10, IL1-RA) contributing to prevention of apoptosis, increasing cell proliferation in the liver (increase of PCNA) gene expression) which might correct liver dysfunction. MSCs are potent candidates to repair and protect healthy tissues against radiation damages.
Highlights
Multipotent stromal cells, named mesenchymal stromal cells or mesenchymal stem cells (MSCs), are capable of dividing and their progenies are further capable of differentiating into one of several mesenchymal phenotypes, such as osteoblasts, chondrocytes, myocytes, marrow stromal cells, tendon-ligament fibroblasts, and adipocytes [1]
Irradiation induced an increase of plasmatic transaminases levels, an increase of the apoptosis process in the liver vascular system, and an increase of oxidative stress. Human Bone Marrow-Derived MSC (hMSC) injection decreased transaminases levels, oxidative stress, and apoptotic cells and may reduce ROS production in the injured liver
Seven days after total body irradiation (TBI), the urea level was significantly lower in irradiated mice than in non irradiated mice or in mice irradiated and injected with hMSCs
Summary
Multipotent stromal cells, named mesenchymal stromal cells or mesenchymal stem cells (MSCs), are capable of dividing and their progenies are further capable of differentiating into one of several mesenchymal phenotypes, such as osteoblasts, chondrocytes, myocytes, marrow stromal cells, tendon-ligament fibroblasts, and adipocytes [1]. We showed that in a mice model the presence of intravenously injected MSCs increased in damaged tissues following radiation exposure [7, 8] and that in a nonhuman primate model MSCs could be detected in regenerating tissues [4]. It has been shown that MSCs infusion engraftment in the liver facilitates recovery from chemically induced acute liver damage as well as recovery by an indirect effect after radiation injury [28–32]. These MSCs differentiate in hepatocyte-like cells and secrete a variety of cytokines and growth factors that have both paracrine and autocrine activities. MSCs have implications for treatment of allograft rejection, graft-versus-host disease, autoimmune inflammatory bowel disease, and other disorders in which immunomodulation and tissue repair are required
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