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microRNA-150 regulates mobilization and migration of bone marrow-derived mononuclear cells by targeting Cxcr4.

Tano N, Kim HW, Ashraf M - PLoS ONE (2011)

Bottom Line: Our results show that miR-150/CXCR4 cascade enhances MNC mobilization and migration.To show that miR-150 regulates MNC mobilization, knockdown of miR-150 in BM-MNCs by specific antisense inhibitor resulted in their higher migration ability in vitro as compared to scramble-transfected MNCs.In conclusion, this study demonstrates that ischemia mobilizes BM stem cells via miR-150/CXCR4 dependent mechanism and miR-150 may be a novel therapeutic target for stem cell migration to the ischemic tissue for neovascularization and repair.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Lab Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America.

ABSTRACT
The interaction between chemokine receptor type 4 (CXCR4) and its ligand, stromal cell-derived factor (SDF)-1, plays an important role in stem cell mobilization and migration in ischemic tissues. MicroRNAs (miRs) are key regulators of stem cell function and are involved in regulation of stem cell survival and differentiation to adopt different cell lineages. In this study, we show that ischemia inhibits the expression of miR-150 in BM-derived mononuclear cells (MNC) and activates its target Cxcr4 gene. Our results show that miR-150/CXCR4 cascade enhances MNC mobilization and migration. By using mouse acute myocardial infarction (MI) model, we found that MNCs in peripheral blood (PB) were increased significantly at day 5 after AMI as compared to control group and the number of CXCR4 positive MNCs both in bone marrow (BM) and PB was also markedly increased after MI. Analysis by microarray-based miRNA profiling and real-time PCR revealed that the expression of miR-150 which targets Cxcr4 gene as predicted was significantly downregulated in BM-MNCs after MI. Abrogation of miR-150 markedly increased CXCR4 protein expression suggesting its target gene. To show that miR-150 regulates MNC mobilization, knockdown of miR-150 in BM-MNCs by specific antisense inhibitor resulted in their higher migration ability in vitro as compared to scramble-transfected MNCs. Furthermore, in vivo BM transplantation of MNCs lacking miR-150 expression by lentiviral vector into the irradiated wild type mice resulted in the increased number of MNCs in PB after AMI as compared to control. In conclusion, this study demonstrates that ischemia mobilizes BM stem cells via miR-150/CXCR4 dependent mechanism and miR-150 may be a novel therapeutic target for stem cell migration to the ischemic tissue for neovascularization and repair.

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Microarray-based miRs expression profiling in BM-MNCs.(A) Gene tree represented on left and heat map on right of 15 experiments, respectively (n = 5). The color of the top bar shows the degree of expression (red; upregulated genes, green; downregulated genes). (B) The list of miRs whose expression was altered in BM-MNCs in response to LAD ligation.
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pone-0023114-g002: Microarray-based miRs expression profiling in BM-MNCs.(A) Gene tree represented on left and heat map on right of 15 experiments, respectively (n = 5). The color of the top bar shows the degree of expression (red; upregulated genes, green; downregulated genes). (B) The list of miRs whose expression was altered in BM-MNCs in response to LAD ligation.

Mentions: To examine the potential participation of miRs in mobilization of MNCs, we performed miR profiling in BM-derived MNCs by using miRs microarray. As shown in Figure 2A and B, specific sets of miRs expression decreases more than 2 folds in BM-MNCs from AMI mice at 3 days as compared to control mice. These include miR-1937a (−3.6 fold), miR-494 (−3.39 fold), miR-29c (−3.19 fold), miR-150 (−2.95 fold), miR-486 (−2.37 fold), miR-30c (−2.35 fold) and miR-30b (−2.14 fold). Interestingly, miR-29c, miR-150, and miR-494 expression was further decreased more than 4 fold at 5 days (−7.28, −4.75, and −4.27, respectively), which led us to further study the role of these miRNAs in MNC mobilization.


microRNA-150 regulates mobilization and migration of bone marrow-derived mononuclear cells by targeting Cxcr4.

Tano N, Kim HW, Ashraf M - PLoS ONE (2011)

Microarray-based miRs expression profiling in BM-MNCs.(A) Gene tree represented on left and heat map on right of 15 experiments, respectively (n = 5). The color of the top bar shows the degree of expression (red; upregulated genes, green; downregulated genes). (B) The list of miRs whose expression was altered in BM-MNCs in response to LAD ligation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198444&req=5

pone-0023114-g002: Microarray-based miRs expression profiling in BM-MNCs.(A) Gene tree represented on left and heat map on right of 15 experiments, respectively (n = 5). The color of the top bar shows the degree of expression (red; upregulated genes, green; downregulated genes). (B) The list of miRs whose expression was altered in BM-MNCs in response to LAD ligation.
Mentions: To examine the potential participation of miRs in mobilization of MNCs, we performed miR profiling in BM-derived MNCs by using miRs microarray. As shown in Figure 2A and B, specific sets of miRs expression decreases more than 2 folds in BM-MNCs from AMI mice at 3 days as compared to control mice. These include miR-1937a (−3.6 fold), miR-494 (−3.39 fold), miR-29c (−3.19 fold), miR-150 (−2.95 fold), miR-486 (−2.37 fold), miR-30c (−2.35 fold) and miR-30b (−2.14 fold). Interestingly, miR-29c, miR-150, and miR-494 expression was further decreased more than 4 fold at 5 days (−7.28, −4.75, and −4.27, respectively), which led us to further study the role of these miRNAs in MNC mobilization.

Bottom Line: Our results show that miR-150/CXCR4 cascade enhances MNC mobilization and migration.To show that miR-150 regulates MNC mobilization, knockdown of miR-150 in BM-MNCs by specific antisense inhibitor resulted in their higher migration ability in vitro as compared to scramble-transfected MNCs.In conclusion, this study demonstrates that ischemia mobilizes BM stem cells via miR-150/CXCR4 dependent mechanism and miR-150 may be a novel therapeutic target for stem cell migration to the ischemic tissue for neovascularization and repair.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Lab Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America.

ABSTRACT
The interaction between chemokine receptor type 4 (CXCR4) and its ligand, stromal cell-derived factor (SDF)-1, plays an important role in stem cell mobilization and migration in ischemic tissues. MicroRNAs (miRs) are key regulators of stem cell function and are involved in regulation of stem cell survival and differentiation to adopt different cell lineages. In this study, we show that ischemia inhibits the expression of miR-150 in BM-derived mononuclear cells (MNC) and activates its target Cxcr4 gene. Our results show that miR-150/CXCR4 cascade enhances MNC mobilization and migration. By using mouse acute myocardial infarction (MI) model, we found that MNCs in peripheral blood (PB) were increased significantly at day 5 after AMI as compared to control group and the number of CXCR4 positive MNCs both in bone marrow (BM) and PB was also markedly increased after MI. Analysis by microarray-based miRNA profiling and real-time PCR revealed that the expression of miR-150 which targets Cxcr4 gene as predicted was significantly downregulated in BM-MNCs after MI. Abrogation of miR-150 markedly increased CXCR4 protein expression suggesting its target gene. To show that miR-150 regulates MNC mobilization, knockdown of miR-150 in BM-MNCs by specific antisense inhibitor resulted in their higher migration ability in vitro as compared to scramble-transfected MNCs. Furthermore, in vivo BM transplantation of MNCs lacking miR-150 expression by lentiviral vector into the irradiated wild type mice resulted in the increased number of MNCs in PB after AMI as compared to control. In conclusion, this study demonstrates that ischemia mobilizes BM stem cells via miR-150/CXCR4 dependent mechanism and miR-150 may be a novel therapeutic target for stem cell migration to the ischemic tissue for neovascularization and repair.

Show MeSH
Related in: MedlinePlus