Myocardial CXCR4 expression is required for mesenchymal stem cell mediated repair following acute myocardial infarction.
Mice; Myocardium; Cells; Receptors; Proteins; Animal Studies; Cell Physiology; Cardiovascular System Physiology; Myocardial Infarction; Myocardial Infarction – Therapy; Stem Cells – Metabolism; Cytokines – Metabolism; Cell Surface – Metabolism; Myocardial Infarction – Pathology; Apoptosis – Physiology; Cell Movement – Physiology; Cell Surface; Coronary Circulation – Physiology; Gene Expression – Physiology; Stem Cells – Transplantation
BACKGROUND: Overexpression of stromal cell-derived factor-1 in injured tissue leads to improved end-organ function. In this study, we quantify the local trophic effects of mesenchymal stem cell (MSC) stromal cell-derived factor-1 release on the effects of MSC engraftment in the myocardium after acute myocardial infarction. METHODS AND RESULTS: Conditional cardiac myocyte CXCR4 (CM-CXCR4) null mice were generated by use of tamoxifen-inducible cardiac-specific cre by crossing CXCR4 floxed with MCM-cre mouse. Studies were performed in littermates with (CM-CXCR4 null) or without (control) tamoxifen injection 3 weeks before acute myocardial infarction. One day after acute myocardial infarction, mice received 100 000 MSC or saline via tail vein. We show [alpha]-myosin heavy chain MerCreMer and the MLC-2v promoters are active in cardiac progenitor cells. MSC engraftment in wild-type mice decreased terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling positive CM (-44%, P\textless0.01), increased cardiac progenitor cell recruitment (100.9%, P\textless0.01), and increased cardiac myosin-positive area (39%, P\textless0.05) at 4, 7, and 21 days after acute myocardial infarction, respectively. MSC in wild-type mice resulted in 107.4% (P\textless0.05) increase in ejection fraction in comparison with 25.9% (P=NS) increase in CM-CXCR4 null mice. These differences occurred despite equivalent increases (16%) in vascular density in response to MSC infusion in wild-type and CM-CXCR4 null mice. CONCLUSIONS: These data demonstrate that the local trophic effects of MSC require cardiac progenitor cell and CM-CXCR4 expression and are mediated by MSC stromal cell-derived factor-1 secretion. Our results further demonstrate and quantify for the first time a specific paracrine mechanism of MSC engraftment. In the absence of CM-CXCR4 expression, there is a significant loss of functional benefit in MSC-mediated repair despite equal increases in vascular density.
Dong F; Harvey J; Finan A; Weber K; Agarwal U; Penn M S
Circulation
2012
2012-07-17
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1161/circulationaha.111.082453" target="_blank" rel="noreferrer noopener">10.1161/circulationaha.111.082453</a>
Lipopolysaccharide supports maintaining the stemness of CD133(+) hepatoma cells through activation of the NF-kappaB/HIF-1alpha pathway.
*Cancer stem cells; *Lipopolysaccharide; *Plasticity; *Stemness maintenance; *Tumor microenvironment; AC133 Antigen/genetics/*metabolism; alpha Subunit/genetics/*metabolism; Animals; Antineoplastic Agents – Pharmacodynamics; Antineoplastic Agents/pharmacology; Body Weights and Measures; Carcinoma; Cell Line; Cell Movement – Drug Effects; Cell Movement/drug effects; Cell Physiology; Cell Physiology – Drug Effects; Cell Proliferation/drug effects; Drug Resistance; Gene Expression Regulation; Genes; Genetic Techniques; Hepatocellular; Hepatocellular – Drug Therapy; Hepatocellular – Metabolism; Hepatocellular – Pathology; Hepatocellular/drug therapy/genetics/*metabolism/pathology; Humans; Hypoxia-Inducible Factor 1; Inbred BALB C; Lipopolysaccharides – Pharmacodynamics; Lipopolysaccharides/*pharmacology; Liver Neoplasms; Liver Neoplasms – Drug Therapy; Liver Neoplasms – Metabolism; Liver Neoplasms – Pathology; Liver Neoplasms/drug therapy/genetics/*metabolism/pathology; Male; Mice; Neoplasm; Neoplasm Invasiveness; Neoplastic; Neoplastic Stem Cells/*drug effects/metabolism/pathology; NF-kappa B – Metabolism; NF-kappa B/*metabolism; Nude; Phenotype; Proteins; Proteins – Metabolism; RNA Interference; Signal Transduction – Drug Effects; Signal Transduction/drug effects; Stem Cells – Drug Effects; Stem Cells – Metabolism; Stem Cells – Pathology; Time Factors; Transfection; Tumor Burden; Tumor Microenvironment
Due to the existence of cancer stem cells (CSCs), persistence and relapse of human hepatocellular carcinoma (HCC) are common after treatment with existing anti-cancer therapies. Emerging evidence indicates that lipopolysaccharide (LPS) plays a crucial role in aggravating HCC, but information about the effect of LPS on CSCs of HCC remains scant. Here, we report that the stemness of CD133(+) CSCs sorted from the human HCC cell line Huh7 was maintained well when cells were cultured with LPS. The reduction of CD133 expression was much lesser in cultured CSCs in the presence of LPS. In response to LPS stimulation, CSCs showed an increase in their activity of clonogenesis and tumorigenesis. LPS also supported maintaining CSC abilities of migration, invasion, and chemo-resistance. Treatment with HIF-1alpha-specific siRNA significantly reduced CD133 expression by CSCs at both mRNA and protein levels. Further, the expression of HIF-1alpha and CD133 was reduced in LPS-stimulated CSCs when the NF-kappaB inhibitor was added to the cell culture. HIF-1alpha-specific siRNA also effectively counteracted the effect of LPS on maintaining CSC abilities of migration and invasion. These data indicate that LPS, an important mediator in the liver tumor microenvironment, supports the maintenance of CSC stemness through signaling of the NF-kappaB/HIF-1alpha pathway. Our current study highlights LPS as a potential target for developing new therapeutic approaches to eliminate CSCs during the treatment of HCC.
Lai Fo-Bao; Liu Wen-Ting; Jing Ying-Ying; Yu Guo-Feng; Han Zhi-Peng; Yang Xue; Zeng Jian-Xing; Zhang Hang-Jie; Shi Rong-Yu; Li Xiao-Yong; Pan Xiao-Rong; Li Rong; Zhao Qiu-Dong; Wu Meng-Chao; Zhang Ping; Liu Jing-Feng; Wei Li-Xin
Cancer letters
2016
2016-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.canlet.2016.05.014" target="_blank" rel="noreferrer noopener">10.1016/j.canlet.2016.05.014</a>