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

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 ?-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-1? (IL-1?) 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-1? 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.

SUBMITTER: Chang P

PROVIDER: S-EPMC5833479 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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

Chang Pengyu P Zhang Boyin B Shao Lihong L Song Wei W Shi Weiyan W Wang Libo L Xu Tiankai T Li Dong D Gao Xiuzhu X Qu Yaqin Y Dong Lihua L Wang Jin J

Cell death & disease 20180205 2

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 ...[more]

PMID: 29402989

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Project description:BACKGROUND:The use of microRNAs in the therapy of kidney disease is hampered by the difficulties in their effective delivery. Micro-vesicles (MVs) are known as natural carriers of small RNAs. Our prior research has demonstrated that MVs isolated from mesenchymal stem cells (MSCs) are capable of attenuating kidney injuries induced by unilateral ureteral obstruction and 5/6 sub-total nephrectomy in mice. The present study aimed to evaluate the effects of miR-34a-5p (miR-34a)-modified MSC-MVs on transforming growth factor (TGF)-?1-induced fibrosis and apoptosis in vitro. METHODS:Bone marrow MSCs were modified by lentiviruses over-expressing miR-34a, from which MVs were collected for the treatment of human Kidney-2 (HK-2) renal tubular cells exposed to TGF-?1 (6?ng/mL). The survival of HK-2 cells was determined using 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) and Annexin V-Light 650/propidium iodide (PI) assays. The expression levels of epithelial markers (tight junction protein 1 [TJP1] and E-cadherin) and mesenchymal markers (smooth muscle actin alpha (?-SMA) and fibronectin) in HK-2 cells were measured using Western blot analysis and an immunofluorescence assay. In addition, changes in Notch-1/Jagged-1 signaling were analyzed using Western blotting. Data were analyzed using a Student's t test or one-way analysis of variance. RESULTS:MiR-34a expression increased three-fold in MVs generated by miR-34a-modified MSCs compared with that expressed in control MVs (P?<?0.01, t?=?16.55). In HK-2 cells, TJP1 and E-cadherin levels decreased to 31% and 37% after treatment with TGF-?1, respectively, and were restored to 62% and 70% by miR-34a-enriched MSC-MVs, respectively. The expression of ?-SMA and fibronectin increased by 3.9- and 5.0-fold following TGF-?1 treatment, and decreased to 2.0- and 1.7-fold after treatment of HK-2 cells with miR-34a-enriched MSC-MVs. The effects of miR-34a-enriched MSC-MVs on epithelial-mesenchymal transition (EMT) markers were stronger than control MSC-MVs. The effects of miR-34a-enriched MSC-MVs on these EMT markers were stronger than control MSC-MVs. Notch-1 receptor and Jagged-1 ligand, two major molecules of Notch signaling pathway, are predicted targets of miR-34a. It was further observed that elevation of Notch-1 and Jagged-1 induced by TGF-?1 was inhibited by miR-34a-enriched MSC-MVs. In addition, TGF-?1 exposure also induced apoptosis in HK-2 cells. Although miR-34a-mofidied MSC-MVs were able to inhibit TGF-?1-triggered apoptosis in HK-2 cells, the effects were less significant than control MSC-MVs (control:TGF-?1: miR-nc-MV:miR-34a-MV?=?1.3:0.6:1.1:0.9 for MTT assay, 1.8%:23.3%:9.4%:17.4% for apoptosis assay). This phenomenon may be the result of the pro-apoptotic effects of miR-34a. CONCLUSIONS:The present study demonstrated that miR-34a-over-expressing MSC-MVs inhibit EMT induced by pro-fibrotic TGF-?1 in renal tubular epithelial cells, possibly through inhibition of the Jagged-1/Notch-1 pathway. Genetic modification of MSC-MVs with an anti-fibrotic molecule may represent a novel strategy for the treatment of renal injuries.

Dataset Information

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

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

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