RESUMO
We show that mouse embryonic endothelial progenitor cells (eEPCs) home preferentially to hypoxic lung metastases when administered intravenously. This specificity is inversely related to the degree of perfusion and vascular density in the metastasis and directly related to local levels of hypoxia and VEGF. Ex vivo expanded eEPCs that were genetically modified with a suicide gene specifically and efficiently eradicated lung metastases with scant patent blood vessels. eEPCs do not express MHC I proteins, are resistant to natural killer cell-mediated cytolysis, and can contribute to tumor vessel formation also in nonsyngeneic mice. These results indicate that eEPCs can be used in an allogeneic setting to treat hypoxic metastases that are known to be resistant to conventional therapeutic regimes.
Assuntos
Hipóxia Celular , Desenvolvimento Embrionário e Fetal/fisiologia , Endotélio Vascular/embriologia , Genes Transgênicos Suicidas , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Células-Tronco/fisiologia , Animais , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Neoplasias Ósseas/terapia , Efeito Espectador , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patologia , Carcinoma Pulmonar de Lewis/terapia , Citosina Desaminase/genética , Citosina Desaminase/metabolismo , Endotélio Vascular/metabolismo , Fluoruracila/metabolismo , Marcação de Genes , Terapia Genética , Vetores Genéticos , Injeções Intravenosas , Células Matadoras Naturais/metabolismo , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Neovascularização Patológica/prevenção & controle , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Osteossarcoma/terapia , Pentosiltransferases/genética , Pentosiltransferases/metabolismo , Pró-Fármacos/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/farmacologia , Taxa de Sobrevida , Uracila/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Clonal embryonic endothelial progenitor cells (eEPCs) isolated from embryonic day 7.5 mice home specifically to hypoxic areas in mouse tumor metastases but spare normal organs and do not form carcinomas. Based on these results, we assessed the potential of eEPCs to enhance vascularization and limit organ dysfunction after ischemia in syngenic and xenotypic organisms. The angiogenic potential of eEPCs was evaluated in chronic ischemic rabbit hindlimbs after regional application by retroinfusion. eEPC treatment improved limb perfusion, paralleled by an increase in capillary density and collateral blood vessel number. Systemic eEPC infusion into mice after ischemic cardiac insult increased postischemic heart output measured by a marked improvement in left ventricle developed pressure and both systolic and diastolic functions. In vitro, eEPCs strongly induced vascular outgrowths from aortic rings. To address the molecular basis of this intrinsic angiogenic potential, we investigated the eEPC transcriptome. Genome-wide Affymetrix GeneChip analysis revealed that the eEPCs express a wealth of secreted factors known to induce angiogenesis, tissue remodeling, and organogenesis that may contribute to the eEPC-mediated beneficial effects. Our findings show that eEPCs induce blood vessel growth and cardioprotection in severe ischemic conditions providing a readily available source to study the mechanisms of neovascularization and tissue recovery.