MSC-derived cytokines repair radiation-induced intra-villi microvascular injury

// Peng-Yu Chang 1, 2 , Bo-Yin Zhang 3 , Shuang Cui 2 , Chao Qu 2 , Li-Hong Shao 2 , Tian-Kai Xu 2 , Ya-Qin Qu 2 , Li-Hua Dong 2 and Jin Wang 1, 4 1 State Key Laboratory of Electroanalytical Chemistry, Chinese Academy of Sciences, Changchun Jilin 130022, P.R. China 2 Department of Radiation Oncology, First Bethune Hospital of Jilin University, Changchun 130021, P.R. China 3 Department of Orthopedic Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, P.R. China 4 Department of Chemistry and Physics, State University of New York at Stony Brook, Stony Brook, NY 11794-3400, USA Correspondence to: Jin Wang, email: jin.wang.1@stonybrook.edu Li-Hua Dong, email: drlhdong@163.com Keywords: mesenchymal stem cell, radiation-induced intestinal injury, cytokine therapy Received: April 19, 2017      Accepted: August 26, 2017      Published: September 23, 2017 ABSTRACT Microvascular injury initiates the pathogenesis of radiation enteropathy. As previously demonstrated, the secretome from mesenchymal stem cells contains various angiogenic cytokines that exhibited therapeutic potential for ischemic lesions. As such, the present study aimed to investigate whether cytokines derived from mesenchymal stem cells can repair endothelial injuries from irradiated intestine. Here, serum-free medium was conditioned by human adipose-derived mesenchymal stem cells, and we found that there were several angiogenic cytokines in the medium, including IL-8, angiogenin, HGF and VEGF. This medium promoted the formation of tubules between human umbilical cord vein endothelial cells and protected these cells against radiation-induced apoptosis in vitro . Likewise, our in vivo results revealed that repeated injections of mesenchymal stem cell-conditioned medium could accelerate the recovery of irradiated mice by reducing the serum levels of pro-inflammatory cytokines, including IL-1α, IL-6 and TNF-α, and promoting intra-villi angiogenesis. Herein, intervention by conditioned medium could increase the number of circulating endothelial progenitors, whereas neutralizing SDF-1α and/or inhibiting PI3K would hamper the recruitment of endothelial progenitors to the injured sites. Such results suggested that SDF-1α and PI3K-mediated phosphorylation were required for intra-villi angiogenesis. To illustrate this, we found that conditioned medium enabled endothelial cells to increase intracellular levels of phosphorylated Akt Ser473, both under irradiated and steady state conditions, and to up-regulate the expression of the CXCR4 and CXCR7 genes. Collectively, the present results revealed the therapeutic effects of mesenchymal stem cell-derived cytokines on microvascular injury of irradiated intestine.