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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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AMI increases the numbers of BM-MNCs and CXCR4 positive MNCs.(A) MNCs were isolated at 1, 3 and 5 days after left anterior descending artery ligation (LAD) and analyzed for molecular characterization. (B) The number of PB-MNCs decreased at one day after LAD ligation and increased gradually up to 5 days (n≥10 in each groups). (C) The percentage of CXCR4 positive cells in MNCs increased in both PB and BM after LAD ligation as compared to control. (n = 8 in control group and n = 6 in AMI group). (D) Densitometric analysis of CXCR4 positive MNCs counted after LAD ligation.
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pone-0023114-g001: AMI increases the numbers of BM-MNCs and CXCR4 positive MNCs.(A) MNCs were isolated at 1, 3 and 5 days after left anterior descending artery ligation (LAD) and analyzed for molecular characterization. (B) The number of PB-MNCs decreased at one day after LAD ligation and increased gradually up to 5 days (n≥10 in each groups). (C) The percentage of CXCR4 positive cells in MNCs increased in both PB and BM after LAD ligation as compared to control. (n = 8 in control group and n = 6 in AMI group). (D) Densitometric analysis of CXCR4 positive MNCs counted after LAD ligation.

Mentions: To examine whether AMI induces MNC mobilization from BM into PB, we assessed the number of MNCs in PB from mice at 1, 3 and 5 days after AMI and control mice as shown in Fig. 1A. The numbers of MNCs in PB were significantly decreased at day 1 after AMI (38.6% decrease) and markedly increased at day 3 (47.0% increase) and day 5 (110.7% increase) after AMI (Figure 1B). Furthermore, the percentage of CXCR4 positive MNCs isolated from both PB and BM of AMI mice was significantly increased (2.2 and 2.6 fold, respectively) as compared to those of non-infarcted mice (Figure 1C and D), indicating AMI induces mobilization of MNCs as well as CXCR4+ cells into blood circulation.


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

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

AMI increases the numbers of BM-MNCs and CXCR4 positive MNCs.(A) MNCs were isolated at 1, 3 and 5 days after left anterior descending artery ligation (LAD) and analyzed for molecular characterization. (B) The number of PB-MNCs decreased at one day after LAD ligation and increased gradually up to 5 days (n≥10 in each groups). (C) The percentage of CXCR4 positive cells in MNCs increased in both PB and BM after LAD ligation as compared to control. (n = 8 in control group and n = 6 in AMI group). (D) Densitometric analysis of CXCR4 positive MNCs counted after LAD ligation.
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Related In: Results  -  Collection

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

pone-0023114-g001: AMI increases the numbers of BM-MNCs and CXCR4 positive MNCs.(A) MNCs were isolated at 1, 3 and 5 days after left anterior descending artery ligation (LAD) and analyzed for molecular characterization. (B) The number of PB-MNCs decreased at one day after LAD ligation and increased gradually up to 5 days (n≥10 in each groups). (C) The percentage of CXCR4 positive cells in MNCs increased in both PB and BM after LAD ligation as compared to control. (n = 8 in control group and n = 6 in AMI group). (D) Densitometric analysis of CXCR4 positive MNCs counted after LAD ligation.
Mentions: To examine whether AMI induces MNC mobilization from BM into PB, we assessed the number of MNCs in PB from mice at 1, 3 and 5 days after AMI and control mice as shown in Fig. 1A. The numbers of MNCs in PB were significantly decreased at day 1 after AMI (38.6% decrease) and markedly increased at day 3 (47.0% increase) and day 5 (110.7% increase) after AMI (Figure 1B). Furthermore, the percentage of CXCR4 positive MNCs isolated from both PB and BM of AMI mice was significantly increased (2.2 and 2.6 fold, respectively) as compared to those of non-infarcted mice (Figure 1C and D), indicating AMI induces mobilization of MNCs as well as CXCR4+ cells into blood circulation.

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