CXCR4 Expression Determines Functional Activity of Bone Marrow–Derived Mononuclear Cells for Therapeutic Neovascularization in Acute Ischemia

Seeger, Florian; Rasper, Tina; Koyanagi, Masamichi; Fox, Henrik; Zeiher, Andreas M.; Dimmeler, Stefanie

doi:10.1161/atvbaha.109.194688

Cited by 81 publications

(75 citation statements)

References 60 publications

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“…37,38 IGF-1 additionally stimulates endogenous regeneration and increased the number and differentiation of coinjected cardiac stem cells. 39 BMCs secrete IGF-1 in vitro, 27 and administration of BMCs increased the expression of IGF-1 mRNA in infarcted hearts ( Figure 4A and 4B). Of note, consistent with previous studies, 29 transplanted BMC directly provided IGF-1 as demonstrated by the increased expression of human IGF-1 mRNA, but also induced a longer-term expression of host tissue-derived murine IGF-1 mRNA, suggesting that BMC therapy directly and indirectly stimulated IGF-1 expression in the infarcted tissue.…”

Section: Discussionmentioning

confidence: 96%

“…BMC supernatants significantly suppressed the H 2 O 2 -induced upregulation of miR-34a and reduced cardiomyocyte apoptosis ( Figure 2B and 2C). To identify the factor(s) that mediate the protective effect of BMC supernatants, the antiapoptotic cytokines IGF-1 and hepatocyte growth factor, which are known to be released by BMC, 27 were blocked by neutralizing antibodies. The antiapoptotic effect of BMC supernatants on miR-34a expression and apoptosis was significantly reversed by a neutralizing antibody directed against IGF-1, whereas anti-hepatocyte growth factor antibodies had no effect ( Figure 2B and 2C).…”

Section: Bmc Supernatants Inhibit Cardiac Myocyte Mir-34a Expression mentioning

confidence: 99%

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Regulation of Cardiac MicroRNAs by Bone Marrow Mononuclear Cell Therapy in Myocardial Infarction

et al. 2012

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Background-Cell therapy with bone marrow-derived mononuclear cells (BMCs) can improve recovery of cardiac function after ischemia; however, the molecular mechanisms are not yet fully understood. MicroRNAs (miRNAs) are key regulators of gene expression and modulate the pathophysiology of cardiovascular diseases. Methods and Results-We demonstrated that intramyocardial delivery of BMCs in infarcted mice regulates the expression of cardiac miRNAs and significantly downregulates the proapoptotic miR-34a. In vitro studies confirmed that the supernatant of BMC inhibited the expression of H 2 O 2 -induced miR-34a and cardiomyocytes apoptosis. These effects were blocked by neutralizing antibodies directed against insulin-like growth factor-1 (IGF-1). Indeed, IGF-1 significantly inhibited H 2 O 2 -induced miR-34a expression, and miR-34a overexpression abolished the antiapoptotic effect of IGF-1. Likewise, inhibition of IGF-1 signaling in vivo abolished the BMC-mediated inhibition of miR-34 expression and the protective effect on cardiac function and increased apoptosis and cardiac fibrosis. IGF-1 specifically blocked the expression of the precursor and the mature miR-34a, but did not interfere with the transcription of the primary miR-34a demonstrating that IGF-1 blocks the processing of miR-34a. Conclusions-Together, our data demonstrate that the paracrine regulation of cardiac miRNAs by transplanted BMCs contributes to the protective effects of cell therapy. BMCs release IGF-1, which inhibits the processing of miR-34a, thereby blocking cardiomyocyte apoptosis. Key Words: cell therapy Ⅲ microRNA Ⅲ growth factor Ⅲ myocardial infarction C ell-based therapy is a promising option to treat cardiovascular diseases. Bone marrow-derived mononuclear cells (BMCs) improved the recovery after ischemia in various experimental studies and significantly, although modestly, improved cardiac function in patients after acute myocardial infarction (AMI). 1-3 Multiple mechanisms have been proposed to mediate the therapeutic benefits of BMC therapy, including cell transdifferentiation, cell fusion, and the release of paracrine growth factors and cytokines. 4 In fact, various cytokines and growth factors from transplanted progenitor cells have been shown to elicit positive effects by influencing cardiomyocyte survival, angiogenesis, and the recruitment of endogenous stem cells. 5,6 Moreover, a recent study suggests that c-kitϩ bone marrow-derived cells activate endogenous regeneration. 7 Clinical Perspective on p 1773miRNAs are small noncoding RNAs that negatively modulate gene expression by inhibiting protein translation or inducing degradation of the targeted mRNA. 8 miRNAs play an important role in biological processes during development, tissue homeostasis, and disease. 9 -11 Several miRNAs are regulated after the induction of myocardial infarction (MI) and control neovascularization and fibrosis. [12][13][14] For example, the increased expression of miR-21 and the downregulation of the miR-29 family members have been associated with car...

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Section: Discussionmentioning

confidence: 96%

Section: Bmc Supernatants Inhibit Cardiac Myocyte Mir-34a Expression mentioning

confidence: 99%

Regulation of Cardiac MicroRNAs by Bone Marrow Mononuclear Cell Therapy in Myocardial Infarction

et al. 2012

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“…+ fractions have been observed to be superior to whole CXCR4 -fractions with respect to potential for invasion, neovascularisation, and restoration of perfusion (Seeger et al, 2009).…”

Section: Kuraitis Et Al Controlled Sdf-1 Release For Treating Ischmentioning

confidence: 97%

A stromal cell-derived factor-1 releasing matrix enhances the progenitor cell response and blood vessel growth in ischaemic skeletal muscle

Kuraitis

Zhang²,

Zhang³

et al. 2011

eCM

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Although many regenerative cell therapies are being developed to replace or regenerate ischaemic muscle, the lack of vasculature and poor persistence of the therapeutic cells represent major limiting factors to successful tissue restoration. In response to ischaemia, stromal cellderived factor-1 (SDF-1) is up-regulated by the affected tissue to stimulate stem cell-mediated regenerative responses. Therefore, we encapsulated SDF-1 into alginate microspheres and further incorporated these into an injectable collagen-based matrix in order to improve local delivery. Microsphere-matrix impregnation reduced the time for matrix thermogelation, and also increased the viscosity reached. This double-incorporation prolonged the release of SDF-1, which maintained adhesive and migratory bioactivity, attributed to chemotaxis in response to SDF-1. In vivo, treatment of ischaemic hindlimb muscle with microsphere-matrix led to increased mobilisation of bone marrow-derived progenitor cells, and also improved recruitment of angiogenic cells expressing the SDF-1 receptor (CXCR4) from bone marrow and local tissues. Both matrix and SDF-1-releasing matrix were successful at restoring perfusion, but SDF-1 treatment appeared to play an earlier role, as evidenced by arterioles that are phenotypically older and by increased angiogenic cytokine production, stimulating the generation of a qualitative microenvironment for a rapid and therefore more effi cient regeneration. These results support the release of implanted SDF-1 as a promising method for enhancing progenitor cell responses and restoring perfusion to ischaemic tissues via neovascularisation.

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“…Although current understanding of these processes remains incomplete, two cytokines, SDF-1 and VEGF-A, are thought to be of particular importance to EPC mediated reendothelialization through the stimulation of their cognate receptors: CXCR4 and VEGFR-2, respectively (2,4,14,21,38,51). In the present study, S. typhus vaccination caused a significant increase in VEGF-A; however, this alone was insufficient to mobilize putative EPCs or EC-CFUs.…”

Section: Vegfr-2mentioning

confidence: 99%

Circulating endothelial progenitor cells are not affected by acute systemic inflammation

Padfield¹,

Tura²,

Haeck³

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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Vascular injury causes acute systemic inflammation and mobilizes endothelial progenitor cells (EPCs) and endothelial cell (EC) colony-forming units (EC-CFUs). Whether such mobilization occurs as part of a nonspecific acute phase response or is a phenomenon specific to vascular injury remains unclear. We aimed to determine the effect of acute systemic inflammation on EPCs and EC-CFU mobilization in the absence of vascular injury. Salmonella typhus vaccination was used as a model of acute systemic inflammation. In a double-blind randomized crossover study, 12 healthy volunteers received S. typhus vaccination or placebo. Phenotypic EPC populations enumerated by flow cytometry [CD34+VEGF receptor (VEGF)R-2+CD133+, CD14+VEGFR-2+Tie2+, CD45−CD34+, as a surrogate for late outgrowth EPCs, and CD34+CXCR-4+], EC-CFUs, and serum cytokine concentrations (high sensitivity C-reactive protein, IL-6, and stromal-derived factor-1) were quantified during the first 7 days. Vaccination increased circulating leukocyte (9.8 ± 0.6 vs. 5.1 ± 0.2 × 109cells/l, P < 0.0001), serum IL-6 [0.95 (0–1.7) vs. 0 (0–0) ng/l, P = 0.016], and VEGF-A [60 (45–94) vs. 43 (21–64) pg/l, P = 0.006] concentrations at 6 h and serum high sensitivity C-reactive protein at 24 h [2.7 (1.4–3.6) vs. 0.4 (0.2–0.8) mg/l, P = 0.037]. Vaccination caused a 56.7 ± 7.6% increase in CD14+cells at 6 h ( P < 0.001) and a 22.4 ± 6.9% increase in CD34+cells at 7 days ( P = 0.04). EC-CFUs, putative vascular progenitors, and the serum stromal-derived factor-1 concentration were unaffected throughout the study period ( P > 0.05 for all). In conclusion, acute systemic inflammation causes nonspecific mobilization of hematopoietic progenitor cells, although it does not selectively mobilize putative vascular progenitors. We suggest that systemic inflammation is not the primary stimulus for EPC mobilization after acute vascular injury.

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CXCR4 Expression Determines Functional Activity of Bone Marrow–Derived Mononuclear Cells for Therapeutic Neovascularization in Acute Ischemia

Cited by 81 publications

References 60 publications

Regulation of Cardiac MicroRNAs by Bone Marrow Mononuclear Cell Therapy in Myocardial Infarction

Regulation of Cardiac MicroRNAs by Bone Marrow Mononuclear Cell Therapy in Myocardial Infarction

A stromal cell-derived factor-1 releasing matrix enhances the progenitor cell response and blood vessel growth in ischaemic skeletal muscle

Circulating endothelial progenitor cells are not affected by acute systemic inflammation

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