RESUMO
BACKGROUND: G-CSF based stem cell mobilization and stabilization of cardiac SDF-1 by DPP-IV-inhibition (dual stem cell therapy) improve heart function and survival after myocardial infarction. However, it is barely understood whether this new approach acts specifically through the SDF-1/CXCR4 axis, stimulation of resident cardiac stem cells and improved myocardial perfusion. Therefore, we aimed to clarify the role of the SDF1/CXCR4 axis with respect to the benefits of a dual stem cell based therapy. METHODOLOGY/PRINCIPAL FINDINGS: After surgically induced ligation of the LAD, SDF-1/CXCR4 interactions were specifically blocked by the CXCR4 receptor antagonist AMD3100 in G-CSF and Diprotin A treated C57BL/6 mice. G-CSF+DipA treated and non-treated animals served as controls. Because AMD3100 is known to mobilize bone marrow derived stem cells (BMCs) in high concentrations, the optimal dosage (1.25mg per kg body weight) sufficient to block CXCR4 without stimulating mobilization was established. AMD3100 treatment of G-CSF and Diprotin A stimulated mice significantly decreased myocardial homing of circulating stem cells (FACS analysis) and inverted the beneficial effects of (i) cardiac remodeling (histological analyses), (ii) heart function (Millar tip catheterization) and (iii) survival (Kaplan-Meier curves). G-CSF treatment in combination with DPP-IV inhibition enhanced neovascularization at the infarct border zone which was related to an improved myocardial blood flow as measured by SPECT. Moreover, dual stem cell treatment effectively stimulated the pool of resident cardiac stem cells (FACS) which was reversed by AMD3100 treatment. CONCLUSIONS/SIGNIFICANCE: Our data give final proof that homing through the SDF-1/CXCR-4 axis is essential for the success of dual stem cell therapy.
Assuntos
Quimiocina CXCL12/metabolismo , Mobilização de Células-Tronco Hematopoéticas , Infarto do Miocárdio/terapia , Receptores CXCR4/metabolismo , Transplante de Células-Tronco , Animais , Antígenos CD34/metabolismo , Benzilaminas , Quimiocina CXCL12/antagonistas & inibidores , Ciclamos , Dipeptidil Peptidase 4/metabolismo , Relação Dose-Resposta a Droga , Fator Estimulador de Colônias de Granulócitos/farmacologia , Testes de Função Cardíaca/efeitos dos fármacos , Compostos Heterocíclicos/farmacologia , Antígenos Comuns de Leucócito/metabolismo , Camundongos , Modelos Biológicos , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Neovascularização Fisiológica/efeitos dos fármacos , Oligopeptídeos/farmacologia , Perfusão , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptores CXCR4/antagonistas & inibidores , Análise de SobrevidaRESUMO
Ischemic cardiomyopathy is one of the main causes of death, which may be prevented by stem cell-based therapies. SDF-1alpha is the major chemokine attracting stem cells to the heart. Since SDF-1alpha is cleaved and inactivated by CD26/dipeptidylpeptidase IV (DPP-IV), we established a therapeutic concept--applicable to ischemic disorders in general--by combining genetic and pharmacologic inhibition of DPP-IV with G-CSF-mediated stem cell mobilization after myocardial infarction in mice. This approach leads to (1) decreased myocardial DPP-IV activity, (2) increased myocardial homing of circulating CXCR-4+ stem cells, (3) reduced cardiac remodeling, and (4) improved heart function and survival. Indeed, CD26 depletion promoted posttranslational stabilization of active SDF-1alpha in heart lysates and preserved the cardiac SDF-1-CXCR4 homing axis. Therefore, we propose pharmacological DPP-IV inhibition and G-CSF-based stem cell mobilization as a therapeutic concept for future stem cell trials after myocardial infarction.
