RESUMEN
Multipotent mesenchymal stromal cells (MSCs) represent a rare heterogeneous subset of pluripotent stromal cells that can be isolated from many different adult tissues that exhibit the potential to give rise to cells of diverse lineages. Numerous studies have reported beneficial effects of MSCs in tissue repair and regeneration. After culture expansion and in vivo administration, MSCs home to and engraft to injured tissues and modulate the inflammatory response through synergistic downregulation of proinflammatory cytokines and upregulation of both prosurvival and antiinflammatory factors. In addition, MSCs possess remarkable immunosuppressive properties, suppressing T-cell, NK cell functions, and also modulating dentritic cell activities. Tremendous progress has been made in preclinical studies using MSCs, including the ability to use allogeneic cells, which has driven the application of MSCs toward the clinical setting. This review highlights our current understanding into the biology of MSCs with particular emphasis on the cardiovascular and renal applications, and provides a brief update on the clinical status of MSC-based therapy.
Asunto(s)
Tolerancia Inmunológica/fisiología , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/inmunología , Células del Estroma/inmunología , Animales , Citocinas/inmunología , Citocinas/metabolismo , Humanos , Inflamación/inmunología , Leucocitos/inmunología , Trasplante de Células Madre Mesenquimatosas/tendencias , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Células del Estroma/citología , Células del Estroma/metabolismo , Trasplante Homólogo/métodos , Trasplante Homólogo/tendenciasRESUMEN
BACKGROUND: Arrhythmia occurrence is a variable but serious concern of cell therapy for treating heart failure. Using a rat postinfarction chronic heart failure model, we compared skeletal myoblast (SMB) with bone marrow cell (BMC) injection to highlight donor cell-specific, late-phase arrhythmogenesis and the underlying factors. METHODS AND RESULTS: SMBs or BMCs derived from male GFP-transgenic rats, or PBS were injected intramyocardially into female rat hearts 3 weeks after coronary artery occlusion. At 28 days after injection, echocardiography showed that the left ventricular ejection fraction was significantly improved in both the SMB and BMC groups, compared to PBS control despite poor graft survival as assessed by PCR for the male-specific gene. Radio-telemetry analysis revealed that the SMB group displayed a higher occurrence of ventricular premature contractions with an elongation of the QRS complex and the hearts were more susceptible to isopreterenol-induced ventricular tachycardia compared to the BMC and PBS groups. Western blot and immunoconfocal analysis showed that the gap junction protein, connexin43, was widely and persistently decreased in the SMB group compared to the other groups. IL-1beta was shown to be upregulated in hearts after SMB injection, and in vitro experiments demonstrated that exposure to IL-1beta caused a decrease in connexin43 and intercellular communication in cultured cardiomyocytes. CONCLUSIONS: Although cell therapy was capable of improving function of the postinfarction chronically failing heart, there was late-phase arrhythmogenicity specific to donor cell type. Global downregulation of connexin43 in the host myocardium was indicated to be an important factor underlying late-phase arrhythmogenicity after SMB transplantation.
Asunto(s)
Arritmias Cardíacas/etiología , Conexina 43/metabolismo , Oclusión Coronaria/cirugía , Mioblastos Esqueléticos/trasplante , Miocardio/metabolismo , Complicaciones Posoperatorias , Animales , Animales Modificados Genéticamente , Trasplante de Médula Ósea/métodos , Comunicación Celular , Células Cultivadas , Oclusión Coronaria/diagnóstico por imagen , Oclusión Coronaria/fisiopatología , Regulación hacia Abajo , Ecocardiografía , Electrocardiografía , Femenino , Supervivencia de Injerto , Inyecciones , Interleucina-1beta/metabolismo , Interleucina-1beta/farmacología , Masculino , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/fisiología , Ratas , Ratas Sprague-Dawley , Volumen Sistólico , Regulación hacia Arriba , Complejos Prematuros Ventriculares/etiologíaRESUMEN
BACKGROUND: Inflammation plays an important role in the progress of adverse ventricular remodeling after myocardial infarction. High-mobility group box 1 (HMGB1) is a nuclear protein, which has recently been uncovered to also act as a modifier of inflammation when released. We hypothesized that HMGB1 injection could preferentially modulate local myocardial inflammation, attenuate ventricular remodeling, and subsequently improve cardiac performance of postinfarction chronic heart failure. METHODS AND RESULTS: Three weeks after left coronary artery ligation, HMGB1 (2.5 mug) or PBS was intramyocardially injected into rat hearts. At 28 days after injection, left ventricular ejection fraction was significantly improved after HMGB1 injection compared to PBS (39.3+/-1.4 versus 33.3+/-1.8%; P<0.01). Accumulation of CD45(+) inflammatory cells, two thirds of which were OX62(+) dendritic cells, in the peri-infarct area was significantly attenuated by HMGB1 injection. Dramatic changes in the expression of major proinflammatory cytokines were not detected by microarray or RT-PCR. Adverse ventricular remodeling including cardiomyocyte hypertrophy (cardiomyocyte cross-sectional area; 439+/-7 versus 458+/-6 mum(2); P<0.05) and extracellular collagen deposition (collagen volume fraction; 11.9+/-0.4 versus 15.2+/-0.6%; P<0.01) was attenuated by HMGB1 injection. Analyses of signal transduction pathways revealed that HMGB1 injection activated ERK1/2, but not p38, Akt, and Smad3. Cardiac regeneration and neovascularization were not observed. CONCLUSIONS: HMGB1 injection modulated the local inflammation in the postinfarction chronically failing myocardium, particularly via reducing the accumulation of dendritic cells. This modulated inflammation resulted in attenuated fibrosis and cardiomyocyte hypertrophy, which thereby improved global cardiac function. These data suggest that HMGB1 may be valuable for the chronic heart failure treatment.
Asunto(s)
Proteína HMGB1/administración & dosificación , Insuficiencia Cardíaca/etiología , Infarto del Miocardio/complicaciones , Miocarditis/etiología , Miocarditis/patología , Animales , Enfermedad Crónica , Activación Enzimática , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Proteína HMGB1/farmacología , Corazón/efectos de los fármacos , Corazón/fisiopatología , Insuficiencia Cardíaca/fisiopatología , Hipertrofia , Inyecciones , Miocardio/patología , Miocitos Cardíacos/patología , Ratas , Ratas Sprague-Dawley , Recuperación de la Función , Volumen Sistólico/efectos de los fármacos , Remodelación VentricularRESUMEN
OBJECTIVE: The major immediate-early cytomegalovirus enhancer/promoter (MIECMV), widely used in cardiovascular gene therapy, contains several positively regulatory cAMP response elements (CRE). Catecholamine signaling via beta-adrenoceptors might increase transgene expression from MIECMV, and if so, beta-blockers may have a detrimental effect on the efficacy of clinical cardiovascular gene therapy strategies. METHODS AND RESULTS: Cultured smooth muscle cells were exposed to isoprenaline, atenolol, or propranolol, alone and in combination before infection with adenoviruses expressing beta-galactosidase. beta-galactosidase expression was assayed 72 hours later. Isoprenaline increased transgene expression from MIECMV up to 8-fold (P<0.001), but had no effect on a promoter containing no CRE. The effect of isoprenaline was inhibited by beta-blockade and by specific CRE-decoy oligonucleotides. Beta-blockers did not reduce transgene expression below basal levels. After adenovirus-mediated porcine intracoronary gene transfer, however, beta-blockade reduced beta-galactosidase expression by up to 250-fold compared with non-beta-blocked animals (P<0.01). CONCLUSIONS: Enhancement of promoter activity by endogenous catecholamines is essential for high-level transgene expression from MIECMV within the vasculature. Beta-blocker-mediated suppression of transgene expression from MIECMV in vascular tissues has a significant bearing on clinical studies of cardiovascular gene transfer. This is the first described interaction to our knowledge between widely prescribed pharmaceuticals and a commonly used promoter of clinical transgene expression.