RESUMEN
BACKGROUND: Growth differentiation factor-11 (GDF-11) belongs to the transforming growth factor-ß (TGF-ß) superfamily. To date, the expression of GDF-11 in the ovary and its role in regulating ovarian function are completely unknown. Ovarian granulosa cell-mediated steroidogenesis plays a pivotal role in maintaining normal female reproductive function. GDF-11 and GDF-8 share high sequence similarity and exhibit many similar features and functions. Steroidogenic acute regulatory protein (StAR) regulates the rate-limiting step in steroidogenesis and its expression can be downregulated by GDF-8. Polycystic ovary syndrome (PCOS) is the most common cause of female infertility. The expression levels of GDF-8 are upregulated in the human follicular fluid and granulosa-lutein (hGL) cells of PCOS patients. However, whether similar results can be observed for the GDF-11 needs to be determined. METHODS: The effect of GDF-11 on StAR expression and the underlying molecular mechanisms were explored by a series of in vitro experiments in a primary culture of hGL cells obtained from patients undergoing in vitro fertilization (IVF) treatment. Human follicular fluid samples were obtained from 36 non-PCOS patients and 36 PCOS patients. GDF-11 levels in follicular fluid were measured by ELISA. RESULTS: GDF-11 downregulates StAR expression, whereas the expression levels of the P450 side-chain cleavage enzyme (P450scc) and 3ß-hydroxysteroid dehydrogenase (3ß-HSD) are not affected by GDF-11 in hGL cells. Using pharmacological inhibitors and a siRNA-mediated approach, we reveal that ALK5 but not ALK4 mediates the suppressive effect of GDF-11 on StAR expression. Although GDF-11 activates both SMAD2 and SMAD3 signaling pathways, only SMAD3 is involved in the GDF-11-induced downregulation of StAR expression. In addition, we show that SMAD1/5/8, ERK1/2, and PI3K/AKT signaling pathways are not activated by GDF-11 in hGL cells. RT-qPCR and ELISA detect GDF-11 mRNA expression in hGL cells and GDF-11 protein expression in human follicular fluid, respectively. Interestingly, unlike GDF-8, the expression levels of GDF-11 are not varied in hGL cells and follicular fluid between non-PCOS and PCOS patients. CONCLUSIONS: This study increases the understanding of the biological function of GDF-11 and provides important insights into the regulation of ovarian steroidogenesis.
Asunto(s)
Proteínas Morfogenéticas Óseas/fisiología , Factores de Diferenciación de Crecimiento/fisiología , Células Lúteas/metabolismo , Fosfoproteínas/genética , Adulto , Células Cultivadas , Regulación hacia Abajo/genética , Femenino , Líquido Folicular/metabolismo , Células de la Granulosa/metabolismo , Humanos , Infertilidad Femenina/genética , Infertilidad Femenina/metabolismo , Fosfoproteínas/metabolismo , Síndrome del Ovario Poliquístico/genética , Síndrome del Ovario Poliquístico/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta/metabolismo , Transducción de Señal/fisiología , Proteína smad3/metabolismoRESUMEN
Growth differentiation factor 11 (GDF11) is a transforming factor-ß superfamily member that functions as a negative regulator of neurogenesis during embryonic development. However, when recombinant GDF11 (rGDF11) is administered systemically in aged mice, it promotes neurogenesis, the opposite of its role during development. The goal of the present study was to reconcile this apparent discrepancy by performing the first detailed investigation into the expression of endogenous GDF11 in the adult brain and its effects on neurogenesis. Using quantitative histological analysis, we observed that Gdf11 is most highly expressed in adult neurogenic niches and non-neurogenic regions within the hippocampus, choroid plexus, thalamus, habenula, and cerebellum. To investigate the role of endogenous GDF11 during adult hippocampal neurogenesis, we generated a tamoxifen inducible mouse that allowed us to reduce GDF11 levels. Depletion of Gdf11 during adulthood increased proliferation of neural progenitors and decreased the number of newborn neurons in the hippocampus, suggesting that endogenous GDF11 remains a negative regulator of hippocampal neurogenesis in adult mice. These findings further support the idea that circulating systemic GDF11 and endogenously expressed GDF11 in the adult brain have different target cells or mechanisms of action. Our data describe a role for GDF11-dependent signaling in adult neurogenesis that has implications for how GDF11 may be used to treat CNS disease.
Asunto(s)
Proteínas Morfogenéticas Óseas/fisiología , Factores de Diferenciación de Crecimiento/fisiología , Hipocampo/citología , Proteínas del Tejido Nervioso/fisiología , Neurogénesis/fisiología , Envejecimiento/metabolismo , Animales , Proteínas Morfogenéticas Óseas/biosíntesis , Proteínas Morfogenéticas Óseas/deficiencia , Proteínas Morfogenéticas Óseas/genética , División Celular , Cruzamientos Genéticos , Femenino , Factores de Diferenciación de Crecimiento/biosíntesis , Factores de Diferenciación de Crecimiento/deficiencia , Factores de Diferenciación de Crecimiento/genética , Hipocampo/crecimiento & desarrollo , Hipocampo/metabolismo , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Células-Madre Neurales/metabolismo , Neurogénesis/genética , Especificidad de Órganos , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/genética , Nicho de Células MadreRESUMEN
This study aimed to investigate the role of truncated growth differentiation factor 11 (GDF11), in which the recognition site of Furin from wild-type GDF11 was deleted to enhance the cellular stability, in skin wound healing in the setting of diabetes mellitus (DM) and the underlying mechanisms. Our study found that both truncated and natural GDF11s effectively accelerated wound healing processes in both T1DM and T2DM mice with a potency compatible to PDGF, bFGF, and EGF, but being much higher than GDF8. At the cellular level, GDF11 stimulated the proliferation and suppressed HG-induced apoptosis of HSFs. Further study revealed that GDF11 activated the YAP-Smad2/3-CTGF fibrotic signaling pathway by reversing HG-induced upregulation of phosphorylated form of YAP (p-YAP), increases p-Smad2/3 levels, and restoring HG-induced repression of CTGF expression by GDF11. Overall, the study shows that both natural and truncated GDF11s promote the healing process of skin wound in mice of both T1DM and T2DM partly via stimulating dermal fibrosis via the YAP-Smad2/3-CTGF pathway, suggesting it a potential agent for treating skin wound in diabetic population.
Asunto(s)
Proteínas Morfogenéticas Óseas/administración & dosificación , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Factores de Diferenciación de Crecimiento/administración & dosificación , Cicatrización de Heridas/efectos de los fármacos , Administración Tópica , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Proteínas Morfogenéticas Óseas/fisiología , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Células Cultivadas , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/fisiopatología , Diabetes Mellitus Tipo 1/patología , Diabetes Mellitus Tipo 1/fisiopatología , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/fisiopatología , Fibroblastos/efectos de los fármacos , Fibroblastos/patología , Factores de Diferenciación de Crecimiento/fisiología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Piel/efectos de los fármacos , Piel/lesiones , Piel/patología , Cicatrización de Heridas/fisiologíaRESUMEN
Growth differentiation factor 11 (GDF11), a member of the transforming growth factor-ß (TGF-ß) superfamily, regulates various biological processes in mammals. The effect of GDF11 in brain injury has not been fully elucidated. Our aim was to investigate the effects of GDF11 in cerebral ischemic injury. The expression level of GDF11 increased significantly in the peri-infarct cerebral cortex. Next, the effect of the intracerebroventricular injection of a GDF11 overexpression lentivirus or rGDF11 was investigated in middle cerebral artery occlusion (MCAO) rats. The preventative effects of the GDF11 overexpression virus on stroke were observed. The delivery of the lentivirus into rats before MCAO significantly reduced the infarct volume and the percentage of apoptotic cells and improved motor function in MCAO rats. Furthermore, it elevated the expression of p-Smad2/3 and promoted neurogenesis and angiogenesis in the ipsilateral SVZ during ischemic injury. More importantly, the therapeutic effects of rGDF11 on stroke were subsequently explored. The results in MCAO rats treated with rGDF11 were found similar to that in those treated with the GDF11 overexpression lentivirus. Together, these findings indicate that GDF11 has neuroprotective and neurorestorative effects in cerebral ischemic injury and provide new insights into the function and mechanism of GDF11 in stroke models.
Asunto(s)
Isquemia Encefálica/metabolismo , Factores de Diferenciación de Crecimiento/metabolismo , Animales , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/fisiopatología , Corteza Cerebral , Modelos Animales de Enfermedad , Factores de Diferenciación de Crecimiento/fisiología , Factores de Diferenciación de Crecimiento/uso terapéutico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Masculino , Neovascularización Patológica/tratamiento farmacológico , Neurogénesis , Neuroprotección , Fármacos Neuroprotectores , Ratas , Accidente Cerebrovascular/tratamiento farmacológicoRESUMEN
Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor (TGF)-ß superfamily. The rejuvenative effect of GDF11 has been called into question recently, and its role in liver regeneration is unclear. Here, we investigated the pathophysiologic role of GDF11, as well as its plausible signaling mechanisms in a mouse model of partial hepatectomy (PH). We demonstrated that both serum and hepatic GDF11 protein expression increased following PH. Treatment with adeno-associated viruses-GDF11 and recombinant GDF11 protein severely impaired liver regeneration, whereas inhibition of GDF11 activity with neutralizing antibodies significantly improved liver regeneration after PH. In vitro, GDF11 treatment significantly delayed cell proliferation and induced cell-cycle arrest in α mouse liver 12 (AML12) cells. Moreover, GDF11 activated TGF-ß-SMAD2/3 signaling pathway. Inhibition of GDF11-induced SMAD2/3 activity significantly blocked GDF11-mediated reduction in cell proliferation both in vivo and in vitro. In the clinical setting, GDF11 levels were significantly elevated in patients after hepatectomy. Collectively, these results indicate that rather than a 'rejuvenating' agent, GDF11 impairs liver regeneration after PH. Suppression of cell-cycle progression via TGF-ß-SMAD2/3 signaling pathway may be a key mechanism by which GDF11 inhibits liver regeneration.
Asunto(s)
Proteínas Morfogenéticas Óseas/fisiología , Factores de Diferenciación de Crecimiento/fisiología , Regeneración Hepática/fisiología , Animales , Proteínas Morfogenéticas Óseas/antagonistas & inhibidores , Proteínas Morfogenéticas Óseas/sangre , Proteínas Morfogenéticas Óseas/metabolismo , Proteínas Morfogenéticas Óseas/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Factores de Diferenciación de Crecimiento/antagonistas & inhibidores , Factores de Diferenciación de Crecimiento/sangre , Factores de Diferenciación de Crecimiento/metabolismo , Factores de Diferenciación de Crecimiento/farmacología , Hepatectomía , Hepatocitos/efectos de los fármacos , Hepatocitos/patología , Humanos , Hígado/metabolismo , Hígado/patología , Regeneración Hepática/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Periodo Posoperatorio , Proteínas Recombinantes/farmacología , Transducción de Señal/fisiología , Proteína Smad2/metabolismo , Proteína smad3/metabolismoRESUMEN
Growth differentiation factor 11 (GDF11) is a transforming growth factor ß (TGFß) protein that regulates aspects of central nervous system (CNS) formation and health throughout the lifespan. During development, GDF11 influences CNS patterning and the genesis, differentiation, maturation, and activity of new cells, which may be primarily dependent on local production and action. In the aged brain, exogenous, peripherally delivered GDF11 may enhance neurogenesis and angiogenesis, as well as improve neuropathological outcomes. This is in contrast to a predominantly negative influence on neurogenesis in the developing CNS. Seemingly antithetical effects may correspond to the cell types and mechanisms activated by local versus circulating concentrations of GDF11. Yet undefined, distinct mechanisms of action in young and aged brains may also play a role, which could include differential receptor and binding partner interactions. Exogenously increasing circulating GDF11 concentrations may be a viable approach for improving deleterious aspects of brain aging and neuropathology. Caution is warranted, however, since GDF11 appears to negatively influence muscle health and body composition. Nevertheless, an expanding understanding of GDF11 biology suggests that it is an important regulator of CNS formation and fate, and its manipulation may improve aspects of brain health in older organisms.
Asunto(s)
Proteínas Morfogenéticas Óseas/fisiología , Encéfalo/crecimiento & desarrollo , Factores de Diferenciación de Crecimiento/fisiología , Longevidad/fisiología , Neurogénesis , Factor de Crecimiento Transformador beta/fisiología , Animales , Composición Corporal/efectos de los fármacos , Tipificación del Cuerpo/efectos de los fármacos , Tipificación del Cuerpo/fisiología , Proteínas Morfogenéticas Óseas/genética , Proteínas Morfogenéticas Óseas/farmacología , Encéfalo/metabolismo , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Factores de Diferenciación de Crecimiento/genética , Factores de Diferenciación de Crecimiento/farmacología , Humanos , Desarrollo de Músculos/efectos de los fármacos , Desarrollo de Músculos/fisiología , Miostatina/genética , Miostatina/metabolismo , Neovascularización Fisiológica/efectos de los fármacos , Neovascularización Fisiológica/fisiología , Neurogénesis/efectos de los fármacos , Neurogénesis/fisiología , Homología de Secuencia de Aminoácido , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/farmacologíaRESUMEN
Mesenchymal stem cells (MSCs) are multipotent progenitors that can differentiate into multiple lineages including osteoblastic lineage. Osteogenic differentiation of MSCs is a cascade that recapitulates most, if not all, of the molecular events occurring during embryonic skeletal development, which is regulated by numerous signaling pathways including bone morphogenetic proteins (BMPs). Through a comprehensive analysis of the osteogenic activity, we previously demonstrated that BMP9 is the most potent BMP for inducing bone formation from MSCs both in vitro and in vivo. However, as one of the least studied BMPs, the essential mediators of BMP9-induced osteogenic signaling remain elusive. Here we show that BMP9-induced osteogenic signaling in MSCs requires intact Notch signaling. While the expression of Notch receptors and ligands are readily detectable in MSCs, Notch inhibitor and dominant-negative Notch1 effectively inhibit BMP9-induced osteogenic differentiation in vitro and ectopic bone formation in vivo. Genetic disruption of Notch pathway severely impairs BMP9-induced osteogenic differentiation and ectopic bone formation from MSCs. Furthermore, while BMP9-induced expression of early-responsive genes is not affected by defective Notch signaling, BMP9 upregulates the expression of Notch receptors and ligands at the intermediate stage of osteogenic differentiation. Taken together, these results demonstrate that Notch signaling may play an essential role in coordinating BMP9-induced osteogenic differentiation of MSCs.
Asunto(s)
Factores de Diferenciación de Crecimiento/fisiología , Células Madre Mesenquimatosas/fisiología , Osteogénesis , Receptores Notch/metabolismo , Diferenciación Celular , Factor 2 de Diferenciación de Crecimiento , Células HEK293 , Humanos , Transducción de Señal , Regulación hacia ArribaRESUMEN
BACKGROUND: GDF11 modulates embryonic patterning and kidney organogenesis. Herein, we sought to define GDF11 function in the adult kidney and in renal diseases. METHODS: In vitro renal cell lines, genetic, and murine in vivo renal injury models were examined. RESULTS: Among tissues tested, Gdf11 was highest in normal adult mouse kidney. Expression was increased acutely after 5/6 nephrectomy, ischemia-reperfusion injury, kanamycin toxicity, or unilateral ureteric obstruction. Systemic, high-dose GDF11 administration in adult mice led to renal failure, with accompanying kidney atrophy, interstitial fibrosis, epithelial-to-mesenchymal transition of renal tubular cells, and eventually death. These effects were associated with phosphorylation of SMAD2 and could be blocked by follistatin. In contrast, Gdf11 heterozygous mice showed reduced renal Gdf11 expression, renal fibrosis, and expression of fibrosis-associated genes both at baseline and after unilateral ureteric obstruction compared with wild-type littermates. The kidney-specific consequences of GDF11 dose modulation are direct effects on kidney cells. GDF11 induced proliferation and activation of NRK49f renal fibroblasts and also promoted epithelial-to-mesenchymal transition of IMCD-3 tubular epithelial cells in a SMAD3-dependent manner. CONCLUSION: Taken together, these data suggest that GDF11 and its downstream signals are critical in vivo mediators of renal injury. These effects are through direct actions of GDF11 on renal tubular cells and fibroblasts. Thus, regulation of GDF11 presents a therapeutic target for diseases involving renal fibrosis and impaired tubular function.
Asunto(s)
Proteínas Morfogenéticas Óseas/fisiología , Transición Epitelial-Mesenquimal , Factores de Diferenciación de Crecimiento/fisiología , Nefroesclerosis/etiología , Insuficiencia Renal/etiología , Animales , Línea Celular , Femenino , Folistatina , Riñón/patología , Masculino , Ratones Endogámicos C57BL , Ratones Desnudos , Insuficiencia Renal/patología , Proteína Smad2/metabolismoRESUMEN
PURPOSE: To determine the effect of p38 MAPK signaling pathway on BMP9-induced osteogenetic differentiation of human periodontal ligament stem cells( hPDLSCs)ï¼ METHODSï¼ hPDLSCs were collected in vitro, and adenovirus vectors were used to infect hPDLSCs; then the activity and staining of alkaline phosphatase(ALP) were detected ,the expression of osteopontin (OPN) and osteocalcin(OCN) were detected by qPCR ï¼and the calcium nodule deposition was used to analyse the ability of BMP9-induced hPDLSCs osteogenetic differentiation. Phosphorylation of p38 and MKK3/6 was detected after hPDLSCs was intervened with Ad-BMP9 and SB203580 ( inhibitor of p38 MAPK signaling pathway) for 36 h respectively for the effect of the signaling pathway on osteogenic differentiationï¼ SPSS16.0 software package was used for statistical analysis. RESULTS: Under the action of Ad-BMP9, the activity of ALP, the levels of osteopontin and osteocalcin genes were significantly higher than the control group (P<0.01). Staining of ALP and the calcium nodule deposition were consistent with the activity of ALP, the levels of osteopontin and osteocalcin. Western blot demonstrated that the expression of p-p38 and p-MKK3/6 was increased significantly. After adding SB203580, the expression of ALP, OPN and OCN was decreased significantly (P<0.01),and the calcium mineral deposits were also decreased. CONCLUSIONS: During hPDLSCs differentiation, BMP9 can induce osteogenesis, and MKK3/6-p38-MAPK pathway was involved in the osteogenesis and had positive regulation for osteogenesis of hPDLSCs.
Asunto(s)
Factores de Diferenciación de Crecimiento , Osteogénesis , Ligamento Periodontal , Proteínas Quinasas p38 Activadas por Mitógenos , Diferenciación Celular , Factor 2 de Diferenciación de Crecimiento , Factores de Diferenciación de Crecimiento/fisiología , Humanos , Ligamento Periodontal/citología , Ligamento Periodontal/fisiología , Células Madre , Proteínas Quinasas p38 Activadas por Mitógenos/fisiologíaRESUMEN
Erythropoietin (EPO) plays an essential role in the regulation of erythropoiesis. Its production is under the control of the Hypoxia Inducible Factor (HIF) protein whose stability varies according to the oxygen level. During chronic renal failure, EPO deficiency is the main cause of anemia, but other factors such as iron deficiency and inflammatory syndrome are also involved. More recently, it is hypothesized that other factors such an excess of GDF-11 production may be also involved. Thus, beside Epo treatment HIF and GDF-11 are potentially new therapeutic targets in anemia of chronic kidney disease.
Asunto(s)
Anemia/etiología , Fallo Renal Crónico/complicaciones , Anemia/tratamiento farmacológico , Anemia/fisiopatología , Anemia/terapia , Animales , Proteínas Morfogenéticas Óseas/fisiología , Manejo de la Enfermedad , Modelos Animales de Enfermedad , Eritropoyesis/efectos de los fármacos , Eritropoyesis/fisiología , Eritropoyetina/fisiología , Predicción , Factores de Diferenciación de Crecimiento/fisiología , Humanos , Hipoxia/etiología , Hipoxia/fisiopatología , Hipoxia/prevención & control , Factor 1 Inducible por Hipoxia/fisiología , Inmunoglobulina A/metabolismo , Absorción Intestinal , Deficiencias de Hierro , Hierro de la Dieta/farmacocinética , Ratones , Modelos Biológicos , Receptores de Transferrina/fisiología , Talasemia beta/fisiopatologíaRESUMEN
The mechanisms of aging and senescence include various endogenous and exogenous factors. Among cardiovascular diseases, heart failure is a typical age-related disease. New strategies to restore cardiomyocyte cells have been reported: endogenous substances that can regenerate the heart's cardiomyocytes have been described: follistatin like 1 (FSTL1), growth-differentiation factor 11 (GDF11) and insulin-like growth factor 1 (IGF-I). Manipulation of the different anti and pro- pathways is essential to discover new approaches to regenerative therapies.
Asunto(s)
Envejecimiento , Proteínas Morfogenéticas Óseas/fisiología , Proteínas Relacionadas con la Folistatina/fisiología , Factores de Diferenciación de Crecimiento/fisiología , Factor I del Crecimiento Similar a la Insulina/fisiología , Miocitos Cardíacos/metabolismo , Insuficiencia Cardíaca/metabolismo , Humanos , Regeneración , RejuvenecimientoRESUMEN
Successful bone tissue engineering requires at the minimum sufficient osteoblast progenitors, efficient osteoinductive factors, and biocompatible scaffolding materials. We previously demonstrated that bone morphogenetic protein 9 (BMP9) is one of the most potent factors in inducing osteogenic differentiation of mesenchymal stem cells (MSCs). Here, we investigated the potential use of a biodegradable citrate-based thermosensitive macromolecule, poly(polyethyleneglycol citrate-co-N-isopropylacrylamide) (PPCN) mixed with gelatin (PPCNG) as a scaffold for the delivery of BMP9-stimulated MSCs to promote localized bone formation. The addition of gelatin to PPCN effectively enhanced the cell adhesion and survival properties of MSCs entrapped within the gel in 3D culture. Using the BMP9-transduced MSC line immortalized mouse embryonic fibroblasts (iMEFs), we found that PPCNG facilitated BMP9-induced osteogenic differentiation of iMEFs in vivo and promoted the formation of well-ossified and vascularized trabecular bone-like structures in a mouse model of ectopic bone formation. Histologic evaluation revealed that vascularization of the bony masses retrieved from the iMEFs + PPCNG group was significantly more pronounced than that of the direct cell injection group. Accordingly, vascular endothelial growth factor (VEGF) expression was shown to be significantly higher in the bony masses recovered from the iMEFs + PPCNG group. Taken together, our results suggest that PPCNG may serve as a novel biodegradable and injectable scaffold and carrier for gene and cell-based bone tissue engineering.
Asunto(s)
Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/fisiología , Osteogénesis/fisiología , Ingeniería de Tejidos/métodos , Andamios del Tejido , Resinas Acrílicas/química , Animales , Materiales Biocompatibles/química , Adhesión Celular , Diferenciación Celular/efectos de los fármacos , Supervivencia Celular , Citratos/química , Femenino , Gelatina/química , Factor 2 de Diferenciación de Crecimiento , Factores de Diferenciación de Crecimiento/genética , Factores de Diferenciación de Crecimiento/fisiología , Células HEK293 , Humanos , Ensayo de Materiales , Melanoma Experimental , Ratones , Ratones Desnudos , Polietilenglicoles/química , Temperatura , Andamios del Tejido/química , Transducción GenéticaRESUMEN
Growth differentiation factor 11 (GDF11) and myostatin (or GDF8) are closely related members of the transforming growth factor ß superfamily and are often perceived to serve similar or overlapping roles. Yet, despite commonalities in protein sequence, receptor utilization and signaling, accumulating evidence suggests that these 2 ligands can have distinct functions in many situations. GDF11 is essential for mammalian development and has been suggested to regulate aging of multiple tissues, whereas myostatin is a well-described negative regulator of postnatal skeletal and cardiac muscle mass and modulates metabolic processes. In this review, we discuss the biochemical regulation of GDF11 and myostatin and their functions in the heart, skeletal muscle, and brain. We also highlight recent clinical findings with respect to a potential role for GDF11 and/or myostatin in humans with heart disease. Finally, we address key outstanding questions related to GDF11 and myostatin dynamics and signaling during development, growth, and aging.
Asunto(s)
Proteínas Morfogenéticas Óseas/fisiología , Factores de Diferenciación de Crecimiento/fisiología , Miostatina/fisiología , Adulto , Envejecimiento/fisiología , Secuencia de Aminoácidos , Animales , Proteínas Morfogenéticas Óseas/química , Proteínas Morfogenéticas Óseas/deficiencia , Encéfalo/crecimiento & desarrollo , Encéfalo/fisiología , Dimerización , Femenino , Folistatina/metabolismo , Proteínas Relacionadas con la Folistatina/metabolismo , Factores de Diferenciación de Crecimiento/química , Factores de Diferenciación de Crecimiento/deficiencia , Factores de Diferenciación de Crecimiento/uso terapéutico , Corazón/fisiología , Cardiopatías/metabolismo , Humanos , Masculino , Ratones , Modelos Moleculares , Datos de Secuencia Molecular , Músculos/fisiología , Miocardio/metabolismo , Miostatina/química , Miostatina/deficiencia , Especificidad de Órganos , Conformación Proteica , Estructura Terciaria de Proteína , Ratas , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Transducción de Señal , Relación Estructura-ActividadRESUMEN
Anoikis, a cell death mechanism triggered upon cell-matrix detachment, is regarded as a physiological suppressor of metastasis that can be regulated by a diverse array of signals. The protein encoded by GDF2 is BMP9 and is a member of the bone morphogenetic protein family and the transforming growth factor (TGF) ß superfamily with emerging yet controversial roles in carcinogenesis. In an attempt to identify the function of growth and differentiation factor 2 (GDF2) in epithelial systems, we examined the signaling machinery that is involved and cell fate decisions in response to GDF2 in ovarian and breast epithelia. We find that GDF2 can robustly activate the SMAD1/5 signaling axis by increasing complex formation between the type I receptor serine threonine kinases activin receptor-like kinase (ALK) 3 and ALK6 and the type II receptor serine threonine kinase BMPRII. This activation is independent of cross talk with the SMAD2-transforming growth factor ß pathway. By activating SMAD1/5, epithelial cells regulate anchorage-independent growth by increasing anoikis sensitivity that is dependent on GDF2's ability to sustain the activation of SMAD1/5 via ALK3 and ALK6. Consistent with a role for GDF2 in promoting anoikis susceptibility, the analysis of cell lines and patient data suggests epigenetic silencing of GDF2 in cancer cell lines and increased promoter methylation in patients. These findings collectively indicate an antimetastatic role for GDF2 in ovarian and breast cancer. The work also implicates loss of GDF2 via promoter methylation-mediated downregulation in promotion of carcinogenesis with significant relevance for the use of epigenetic drugs currently in clinical trials.
Asunto(s)
Anoicis/fisiología , Mama/metabolismo , Epigénesis Genética/fisiología , Células Epiteliales/metabolismo , Factores de Diferenciación de Crecimiento/fisiología , Ovario/metabolismo , Animales , Mama/citología , Neoplasias de la Mama/metabolismo , Línea Celular Transformada , Línea Celular Tumoral , Femenino , Factor 2 de Diferenciación de Crecimiento , Células HEK293 , Humanos , Ratones , Neoplasias Ováricas/metabolismo , Ovario/citologíaRESUMEN
Western societies are aging due to an increasing life span, decreased birth rates, and improving social and health conditions. On the other hand, the prevalence of cardiovascular (CV) and cerebrovascular (CBV) diseases rises with age. Thus, in view of the ongoing aging pandemic, it is appropriate to better understand the molecular pathways of aging as well as age-associated CV and CBV diseases. Oxidative stress contributes to aging of organs and the whole body by an accumulation of reactive oxygen species promoting oxidative damage. Indeed, increased oxidative stress produced in the mitochondria and cytosol of heart and brain is a common denominator to almost all CV and CBV diseases. The mitochondrial adaptor protein p66(Shc) and the family of deacetylase enzymes, the sirtuins, regulate the aging process, determine lifespan of many species and are involved in CV diseases. GDF11, a member of TGFß superfamily with homology to myostatin also retards the aging process via yet unknown mechanisms. Recent evidence points towards a promising role of this novel 'rejuvenation' factor in reducing age-related heart disease. Finally, telomere length is also involved in aging and the development of age-related CV dysfunction. This review focuses on the latest scientific advances in understanding age-related changes of the CV and CBV system, as well as delineating potential novel therapeutic targets derived from aging research for CV and CBV diseases.
Asunto(s)
Envejecimiento/fisiología , Enfermedades Cardiovasculares/etiología , Envejecimiento/genética , Animales , Proteínas Morfogenéticas Óseas/fisiología , Restricción Calórica , Radicales Libres/metabolismo , Factores de Diferenciación de Crecimiento/fisiología , Humanos , Longevidad/fisiología , Mitocondrias/fisiología , Modelos Biológicos , Estrés Oxidativo/fisiología , Proteínas Proto-Oncogénicas c-jun/fisiología , Conducta de Reducción del Riesgo , Proteínas Adaptadoras de la Señalización Shc/fisiología , Sirtuinas/fisiología , Proteína Transformadora 1 que Contiene Dominios de Homología 2 de Src , Acortamiento del Telómero/fisiología , Rigidez Vascular/fisiologíaRESUMEN
Skeletal muscle mass, function, and repair capacity all progressively decline with aging, restricting mobility, voluntary function, and quality of life. Skeletal muscle repair is facilitated by a population of dedicated muscle stem cells (MuSCs), also known as satellite cells, that reside in anatomically defined niches within muscle tissues. In adult tissues, MuSCs are retained in a quiescent state until they are primed to regenerate damaged muscle through cycles of self-renewal divisions. With aging, muscle tissue homeostasis is progressively disrupted and the ability of MuSCs to repair injured muscle markedly declines. Until recently, this decline has been largely attributed to extrinsic age-related alterations in the microenvironment to which MuSCs are exposed. However, as highlighted in this Perspective, recent reports show that MuSCs also progressively undergo cell-intrinsic alterations that profoundly affect stem cell regenerative function with aging. A more comprehensive understanding of the interplay of stem cell-intrinsic and extrinsic factors will set the stage for improving cell therapies capable of restoring tissue homeostasis and enhancing muscle repair in the aged.
Asunto(s)
Envejecimiento/fisiología , Músculo Esquelético/citología , Músculo Esquelético/fisiología , Regeneración/fisiología , Células Madre/fisiología , Animales , Proteínas Morfogenéticas Óseas/fisiología , Polaridad Celular , Senescencia Celular , Factores de Diferenciación de Crecimiento/fisiología , Homeostasis , Humanos , Inflamación/fisiopatología , Proteínas Quinasas p38 Activadas por Mitógenos/fisiologíaRESUMEN
BACKGROUND: Neovascularization plays an important role in tissue engineering applications. In animal models, it was demonstrated that implantation of endothelial progenitor cells (EPCs) from cord blood led to the formation of a complex functional neovasculature, whereas EPCs isolated from peripheral blood (pbEPCs) showed a limited vasculogenic potential, which may be attributed to age-related dysfunction. Growth differentiation factor 11 (GDF11) was recently identified as a rejuvenation factor, which was able to reverse age-related dysfunction of stem cells. Therefore, we hypothesized that GDF11 may improve the vasculogenesis-related phenotype of pbEPCs. MATERIALS AND METHODS: pbEPCs were isolated from adult peripheral blood. Transforming growth factor (TGF)-ß type-I receptor expression was analyzed by immunostaining. pbEPCs were treated with recombinant GDF11 for various time periods. Thereafter, phosphorylation of Smad2/Smad3, adhesion, proliferation, cell survival, migration, and in vitro sprout formation was investigated. RESULTS: pbEPCs express the TGF-ß type-I receptors ALK4 and ALK5, but not ALK7. Treatment of pbEPCs with recombinant GDF11 resulted in activation of the Smad2/Smad3 pathway and in increased migration, which was inhibited by the TGF-ß1 superfamily type-I activin receptor-like kinase inhibitor SB431542, demonstrating that the TGF-ß receptor-Smad2/Smad3 pathway is involved in GDF11 induced migration. Moreover, in vitro sprout formation was increased as well by GDF11 treatment. However, other parameters such as adherence, proliferation, and apoptosis were not affected by GDF11. CONCLUSIONS: This study provides evidence that GDF11 improves vasculogenesis-related growth parameters in pbEPCs and may represent a therapeutic option to ameliorate the angiogenic and vasculogenic properties of pbEPCs.