RESUMO
BACKGROUND: Neonatal mesenchymal stem cells exhibit less cardioprotective potential than their adult counterparts. Transforming growth factor-α (TGF-α) has been shown to stimulate adult stem cell VEGF production, however, it remains unknown whether it may augment neonatal stem cell paracrine function. We hypothesized that TGF-α would equalize adult and neonatal stem cell paracrine function and cardioprotection during acute ischemia/reperfusion. MATERIALS AND METHODS: Bone marrow mesenchymal stem cells isolated from adult and 2.5 wk-old mice were treated with TGF-α (250 ng/mL) for 24 h. VEGF, HGF, IGF-1, IL-1ß, and IL-6 production were measure in vitro, and cells were infused via an intracoronary route using a model of isolated heart perfusion. RESULTS: TGF-α equalized adult and neonatal stem cell VEGF production but did not affect production of HGF, IGF-1, IL-1ß, or IL-6. ERK, p38 MAPK, and JNK phosphorylation were greater in adult cells in response to TGF-α. Whereas infusion of adult but not neonatal stem cells was associated with improved myocardial functional recovery during reperfusion, infusions of either TGF-α-pretreated cell group were associated with the greatest functional recovery. TGF-α equalizes adult and neonatal mesenchymal stem cell VEGF production and cardioprotection in association with differential regulation of ERK, p38 MAPK, and JNK phosphorylation.
Assuntos
Células-Tronco Adultas/efeitos dos fármacos , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/terapia , Fator de Crescimento Transformador alfa/farmacologia , Doença Aguda , Células-Tronco Adultas/citologia , Células-Tronco Adultas/metabolismo , Fatores Etários , Animais , Animais Recém-Nascidos , Caspase 3/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/citologia , Miocárdio/metabolismo , Comunicação Parácrina/efeitos dos fármacos , Comunicação Parácrina/fisiologia , Fator de Crescimento Transformador alfa/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Over the past century, numerous animal models have been developed in an attempt to understand myocardial and vascular injury. However, the successful translation of results observed in animals to human therapy remains low. To understand this problem, we present several animal models of cardiac and vascular injury that are of particular relevance to the cardiac or vascular surgeon. We also explore the potential clinical implications and limitations of each model with respect to the human disease state. Our results underscore the concept that animal research requires an in-depth understanding of the model, animal physiology, and the potential confounding factors. Future outcome analyses with standardized animal models may improve translation of animal research from the bench to the bedside.