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Cell Death Dis. 2018 Feb 5;9(2):154. doi: 10.1038/s41419-017-0222-1.

Mesenchymal stem cells over-expressing cxcl12 enhance the radioresistance of the small intestine.

Chang P1,2, Zhang B3, Shao L2, Song W4, Shi W2, Wang L2, Xu T2, Li D5,6, Gao X6,7, Qu Y2, Dong L8, Wang J9,10.

Author information

1
State Key Laboratory of Electroanalytical Chemistry, Chinese Academy of Sciences, 130022, Changchun, China.
2
Department of Radiation Oncology, First Bethune Hospital of Jilin University, 130021, Changchun, China.
3
Department of Orthopedics Surgery, China-Japan Union Hospital of Jilin University, 130033, Changchun, China.
4
Department of Oncology, First Bethune Hospital of Jilin University, 130021, Changchun, China.
5
Department of Immunology, College of Basic Medical Sciences, Jilin University, 130021, Changchun, China.
6
Jilin Province Key Laboratory of Infectious Diseases, Laboratory of Molecular Virology, 130061, Changchun, China.
7
Department of Hepatology, First Bethune Hospital of Jilin University, Jilin University, 130021, Changchun, China.
8
Department of Radiation Oncology, First Bethune Hospital of Jilin University, 130021, Changchun, China. drlhdong@163.com.
9
State Key Laboratory of Electroanalytical Chemistry, Chinese Academy of Sciences, 130022, Changchun, China. jin.wang.1@stonybrook.edu.
10
Department of Chemistry and Physics, State University of New York at Stony Brook, New York, NY, 11794-3400, USA. jin.wang.1@stonybrook.edu.

Abstract

The chemokine C-X-C motif chemokine 12 (CXCL12) greatly impacts various biological processes in mammals, including cell survival, growth and migration. Mesenchymal stem cells (MSCs) are promising tools for carrying foreign genes to treat radiation-induced injuries in the intestinal epithelium. In this study, human adipose-derived MSCs were constructed to over-express the mouse cxcl12 gene to treat such injuries. In vitro, because of the high levels of mouse CXCL12 in conditioned medium produced by mouse cxcl12 gene-modified cells, phosphorylation of Akt at Ser473 and Erk1/2 at Thr202/Thr204 was increased within crypt cells of irradiated organoids compared with unmodified controls. Moreover, intracellular stabilization of β-catenin was achieved after treatment of mouse cxcl12 gene-modified cells with conditioned medium. As a result, survival of crypt cells was maintained and their proliferation was promoted. When delivering mouse cxcl12 gene-modified cells into irradiated BALB/c nude mice, mice were rescued despite the clearance of cells from the host within 1 week. Irradiated mice that received mouse cxcl12 gene-modified MSCs exhibited reduced serum levels of interleukin-1α (IL-1α) and IL-6 as well as elevated levels of CXCL12. Additionally, epithelial recovery from radiation stress was accelerated compared with the irradiated-alone controls. Moreover, mouse cxcl12 gene-modified MSCs were superior to unmodified cells at strengthening host repair responses to radiation stress as well as presenting increased serum CXCL12 levels and decreased serum IL-1α levels. Furthermore, the number of crypt cells that were positive for phosphorylated Akt at Ser473 and phosphorylated Erk1/2 at Thr202/Thr204 increased following treatment with mouse cxcl12 gene-modified MSCs. Thus, cxcl12 gene-modified MSCs confer radioresistance to the intestinal epithelium.

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