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1.
Cardiovasc Res ; 108(3): 377-86, 2015 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-26084310

RESUMEN

AIMS: Neointimal hyperplasia is a common feature of fibro-proliferative vascular disease and characterizes initial stages of atherosclerosis. Neointimal lesions mainly comprise smooth muscle-like cells. The presence of these lesions is related to local differences in shear stress. Neointimal cells may arise through migration and proliferation of smooth muscle cells from the media. However, a role for the endothelium as a source of smooth muscle-like cells has largely been disregarded. Here, we investigated the role of endothelial-to-mesenchymal transition (EndMT) in neointimal hyperplasia and atherogenesis, and studied its modulation by shear stress. METHODS AND RESULTS: In human atherosclerotic plaques and porcine aortic tissues, myo-endothelial cells were identified, suggestive for EndMT. Flow disturbance by thoracic-aortic constriction in mice similarly showed the presence of myo-endothelial cells specifically in regions exposed to disturbed flow. While uniform laminar shear stress (LSS) was found to inhibit EndMT, endothelial cells exposed to disturbed flow underwent EndMT, in vitro and in vivo, and showed atherogenic differentiation. Gain- and loss-of-function studies using a constitutive active mutant of MEK5 and short hairpins targeting ERK5 established a pivotal role for ERK5 signalling in the inhibition of EndMT. CONCLUSION: Together, these data suggest that EndMT contributes to neointimal hyperplasia and induces atherogenic differentiation of endothelial cells. Importantly, we uncovered that EndMT is modulated by shear stress in an ERK5-dependent manner. These findings provide new insights in the role of adverse endothelial plasticity in vascular disease and identify a novel atheroprotective mechanism of uniform LSS, namely inhibition of EndMT.


Asunto(s)
Enfermedades de la Aorta/patología , Arterias Carótidas/patología , Enfermedades de las Arterias Carótidas/patología , Proliferación Celular , Células Endoteliales/patología , Transición Epitelial-Mesenquimal , Mecanotransducción Celular , Placa Aterosclerótica , Remodelación Vascular , Animales , Aorta Torácica/metabolismo , Aorta Torácica/patología , Aorta Torácica/fisiopatología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/metabolismo , Enfermedades de la Aorta/fisiopatología , Arterias Carótidas/metabolismo , Arterias Carótidas/fisiopatología , Enfermedades de las Arterias Carótidas/genética , Enfermedades de las Arterias Carótidas/metabolismo , Enfermedades de las Arterias Carótidas/fisiopatología , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Fibrosis , Células HEK293 , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , MAP Quinasa Quinasa 5/genética , MAP Quinasa Quinasa 5/metabolismo , Masculino , Ratones Endogámicos C57BL , Proteína Quinasa 7 Activada por Mitógenos/genética , Proteína Quinasa 7 Activada por Mitógenos/metabolismo , Neointima , Interferencia de ARN , Flujo Sanguíneo Regional , Estrés Mecánico , Porcinos , Factores de Tiempo , Transfección
2.
Cell Commun Signal ; 11(1): 29, 2013 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-23601247

RESUMEN

BACKGROUND: Macrophages and fibroblasts are two major players in tissue repair and fibrosis. Despite the relevance of macrophages and fibroblasts in tissue homeostasis, remarkably little is known whether macrophages are able to influence the properties of fibroblasts. Here we investigated the role of paracrine factors secreted by classically activated (M1) and alternatively activated (M2) human macrophages on human dermal fibroblasts (HDFs). RESULTS: HDFs stimulated with paracrine factors from M1 macrophages showed a 10 to > 100-fold increase in the expression of the inflammatory cytokines IL6, CCL2 and CCL7 and the matrix metalloproteinases MMP1 and MMP3. This indicates that factors produced by M1 macrophages induce a fibroblast phenotype with pro-inflammatory and extracellular matrix (ECM) degrading properties. HDFs stimulated with paracrine factors secreted by M2 macrophages displayed an increased proliferation rate. Interestingly, the M1-activated pro-inflammatory fibroblasts downregulated, after exposure to paracrine factors produced by M2 macrophages or non-conditioned media, the inflammatory markers as well as MMPs and upregulated their collagen production. CONCLUSIONS: Paracrine factors of M1 or M2 polarized macrophages induced different phenotypes of HDFs and the HDF phenotypes can in turn be reversed, pointing to a high dynamic plasticity of fibroblasts in the different phases of tissue repair.

3.
Circ Heart Fail ; 6(1): 107-17, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23230309

RESUMEN

BACKGROUND: Galectin-3 has been implicated in the development of organ fibrosis. It is unknown whether it is a relevant therapeutic target in cardiac remodeling and heart failure. METHODS AND RESULTS: Galectin-3 knock-out and wild-type mice were subjected to angiotensin II infusion (2.5 µg/kg for 14 days) or transverse aortic constriction for 28 days to provoke cardiac remodeling. The efficacy of the galectin-3 inhibitor N-acetyllactosamine was evaluated in TGR(mREN2)27 (REN2) rats and in wild-type mice with the aim of reversing established cardiac remodeling after transverse aortic constriction. In wild-type mice, angiotensin II and transverse aortic constriction perturbations caused left-ventricular (LV) hypertrophy, decreased fractional shortening, and increased LV end-diastolic pressure and fibrosis (P<0.05 versus control wild type). Galectin-3 knock-out mice also developed LV hypertrophy but without LV dysfunction and fibrosis (P=NS). In REN2 rats, pharmacological inhibition of galectin-3 attenuated LV dysfunction and fibrosis. To elucidate the beneficial effects of galectin-3 inhibition on myocardial fibrogenesis, cultured fibroblasts were treated with galectin-3 in the absence or presence of galectin-3 inhibitor. Inhibition of galectin-3 was associated with a downregulation in collagen production (collagen I and III), collagen processing, cleavage, cross-linking, and deposition. Similar results were observed in REN2 rats. Inhibition of galectin-3 also attenuated the progression of cardiac remodeling in a long-term transverse aortic constriction mouse model. CONCLUSIONS: Genetic disruption and pharmacological inhibition of galectin-3 attenuates cardiac fibrosis, LV dysfunction, and subsequent heart failure development. Drugs binding to galectin-3 may be potential therapeutic candidates for the prevention or reversal of heart failure with extensive fibrosis.


Asunto(s)
Amino Azúcares/uso terapéutico , ADN/genética , Galectina 3/genética , Expresión Génica , Insuficiencia Cardíaca/prevención & control , Miocardio/patología , Remodelación Ventricular , Animales , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/genética , Cardiomiopatías/fisiopatología , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Modelos Animales de Enfermedad , Fibrosis/genética , Fibrosis/metabolismo , Fibrosis/prevención & control , Galectina 3/antagonistas & inhibidores , Galectina 3/biosíntesis , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Inmunohistoquímica , Masculino , Ratones , Ratones Noqueados , Miocardio/metabolismo , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
4.
Immunobiology ; 217(3): 299-306, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22093249

RESUMEN

Macrophages are important in inflammation as well as in tissue repair processes. They can be activated by various stimuli and classified into two major groups: M1 (classically activated) or M2 (alternatively activated). Inflammation, angiogenesis and matrix remodeling play a major role in tissue repair. Here, we investigate the combined influence of a pro-angiogenic microenvironment and specific extracellular matrix (ECM) components or tissue culture polystyrene (TCPS) on the dynamics of human macrophage polarization. We established that human angiogenically primed macrophages cultured on different ECM components exhibit an M2-like polarization. These M2-like macrophages polarized to M1 and M2 macrophages with classical (LPS and IFNγ) stimuli and alternative (IL-4 and IL-13) stimuli respectively. Moreover, these M1 and M2 (primary) polarized macrophages rapidly underwent a secondary (re)polarization to M2 and M1 with conditioned media from M2 and M1 primary polarized macrophages respectively. In these initial priming and later (re)polarization processes the soluble factors had a dominant and orchestrating role, while the type of ECM (collagen I, fibronectin, versus tissue culture polystyrene) did not play a crucial role on the polarization of macrophages.


Asunto(s)
Inductores de la Angiogénesis/metabolismo , Matriz Extracelular/metabolismo , Activación de Macrófagos/inmunología , Macrófagos/metabolismo , Células Cultivadas , Quimiocinas/biosíntesis , Medios de Cultivo Condicionados/farmacología , Citocinas/biosíntesis , Matriz Extracelular/inmunología , Perfilación de la Expresión Génica , Humanos , Factores Inmunológicos/farmacología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Activación de Macrófagos/genética , Macrófagos/efectos de los fármacos , Macrófagos/inmunología
5.
Cardiovasc Res ; 86(3): 506-15, 2010 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-20083576

RESUMEN

AIMS: Reciprocal plasticity exists between endothelial and mesenchymal lineages. For instance, mature endothelial cells adopt a smooth muscle-like phenotype through transforming growth factor beta-1 (TGFbeta1)-driven endothelial-to-mesenchymal transdifferentiation (EndMT). Peripheral blood contains circulating endothelial progenitor cells of which the endothelial colony-forming cells (ECFCs) harbour stem cell-like properties. Given the plasticity between endothelial and mesenchymal lineages and the stem cell-like properties of ECFCs, we hypothesized that ECFCs can give rise to smooth muscle-like progeny. METHODS AND RESULTS: ECFCs were stimulated with TGFbeta1, after which TGFbeta signalling cascades and their downstream effects were investigated. Indeed, EndMT of ECFCs resulted in smooth muscle-like progeniture. TGFbeta1-driven EndMT is mediated by ALK5 kinase activity, increased downstream Smad2 signalling, and reduced protein levels of inhibitor of DNA-binding protein 3. ECFCs lost expression of endothelial markers and endothelial anti-thrombogenic function. Simultaneously, mesenchymal marker expression was gained, cytoskeletal rearrangements occurred, and cells acquired a contractile phenotype. Transdifferentiated ECFCs were phenotypically stable and self-sustaining and, importantly, showed fibroblast growth factor-2 and angiopoietin-1-mediated pro-angiogenic paracrine properties. CONCLUSION: Our study is the first to demonstrate that ECFCs can give rise to smooth muscle-like progeny, with potential therapeutic benefits. These findings further illustrate that ECFCs are highly plastic, which by itself has implications for therapeutical use.


Asunto(s)
Linaje de la Célula , Transdiferenciación Celular , Células Endoteliales/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Neovascularización Fisiológica , Células Madre/metabolismo , Angiopoyetina 1/metabolismo , Biomarcadores/metabolismo , Células Cultivadas , Citoesqueleto/metabolismo , Sangre Fetal/citología , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Humanos , Proteínas Inhibidoras de la Diferenciación/metabolismo , Músculo Liso Vascular/citología , Proteínas de Neoplasias/metabolismo , Comunicación Paracrina , Fenotipo , Proteínas Serina-Treonina Quinasas/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transducción de Señal , Proteína Smad2/metabolismo , Factores de Tiempo , Factor de Crecimiento Transformador beta1/metabolismo , Vasoconstricción
6.
Am J Nephrol ; 30(1): 73-83, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19218792

RESUMEN

BACKGROUND: Ischemia/reperfusion injury (IRI) is a risk factor for the development of interstitial fibrosis. Previously we had shown that after renal IRI, bone marrow-derived cells (BMDC) can differentiate to interstitial myofibroblasts. Here we hypothesized that the immunosuppressant ciclosporin A (CsA), known for its profibrotic side effect, promotes myofibroblast differentiation of BMDC in the postischemic kidney. METHODS: Using a model of unilateral renal IRI in rats reconstituted with R26-human placental alkaline phosphatase transgenic bone marrow, CsA was administered in a previously defined critical window for differentiation of BMDC to myofibroblasts. We evaluated fibrotic changes in the kidney and myofibroblast differentiation of BMDC on day 14 after CsA treatment. RESULTS: CsA treatment for 14 days led to increased transforming growth factor-beta transcript levels and collagen III deposition in the postischemic kidney. However, neither the total number of alpha-smooth-muscle-actin-positive interstitial myofibroblasts, nor the bone marrow-derived fraction thereof was affected by CsA administration, irrespective of dosage and duration of treatment. CONCLUSIONS: In the critical postischemic window of BMDC differentiation to myofibroblasts, CsA did not promote BMDC differentiation to myofibroblasts, suggesting that, in the clinical setting, CsA is not involved in myofibroblastic differentiation of BMDC.


Asunto(s)
Médula Ósea/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Ciclosporina/farmacología , Fibroblastos/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Actinas/metabolismo , Animales , Inhibidores Enzimáticos/farmacología , Humanos , Isquemia , Riñón/patología , Masculino , Músculo Liso/metabolismo , Ratas , Ratas Endogámicas F344 , Células Madre/metabolismo
7.
Transplantation ; 84(8): 1003-11, 2007 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-17989606

RESUMEN

BACKGROUND: In human renal allografts, recipient-derived cells engrafted in various kidney substructures, have been detected in the long term after transplantation. Here we investigated tubular engraftment and myofibroblast differentiation of recipient-derived cells at short term after experimental kidney transplantation, during a previously described window of regeneration and possible onset of renal interstitial fibrosis. METHODS: Fisher (F344, syngeneic) and Dark Agouti (DA, allogeneic) kidneys were transplanted into F344-hPAP transgenic recipient rats, which allowed tracing of recipient-derived cells in nontransgenic donor kidneys. We evaluated tubular engraftment and myofibroblast differentiation of recipient-derived cells on day 14 after kidney transplantation. RESULTS: Kidney transplantation resulted in tubular engraftment of recipient-derived cells. After allogeneic kidney transplantation, 9.7% of tubular cross-sections contained at least one recipient-derived cell, which represented a significant increase in comparison to syngeneic transplantation (4.0%, P<0.05). Moreover, recipient-derived myofibroblasts were present in the renal interstitium of the transplanted kidney. These cells contributed 39% of the total interstitial myofibroblast population in allografts, which was comparable to the syngeneic situation (28%, P=0.25). CONCLUSIONS: In a defined early window of regeneration and possible onset of renal interstitial fibrosis after kidney transplantation, rejection-associated injury, superimposed on ischemic damage, increases tubular engraftment of recipient-derived cells, although it does not affect their relative contribution to the renal interstitial myofibroblast population.


Asunto(s)
Rechazo de Injerto/etiología , Rechazo de Injerto/patología , Trasplante de Riñón/patología , Túbulos Renales/patología , Fosfatasa Alcalina/análisis , Fosfatasa Alcalina/genética , Animales , Animales Modificados Genéticamente , Diferenciación Celular , Colágeno Tipo III/análisis , Fibroblastos/citología , Fibroblastos/enzimología , Fibrosis , Isquemia/patología , Riñón/irrigación sanguínea , Riñón/patología , Riñón/fisiología , Túbulos Renales/fisiología , Masculino , Modelos Animales , Mioblastos/citología , Mioblastos/enzimología , Ratas , Regeneración
8.
J Am Soc Nephrol ; 18(1): 165-75, 2007 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17135399

RESUMEN

Bone marrow-derived cells (BMDC) have been proposed to exert beneficial effects after renal ischemia/reperfusion injury (IRI) by engraftment in the tubular epithelium. However, BMDC can give rise to myofibroblasts and may contribute to fibrosis. BMDC contribution to the renal interstitial myofibroblast population in relation to fibrotic changes after IRI in rats was investigated. A model of unilateral renal IRI (45 min of ischemia) was used in F344 rats that were reconstituted with R26-human placental alkaline phosphatase transgenic BM to quantify BMDC contribution to the renal interstitial myofibroblast population over time. After IRI, transient increases in collagen III transcription and interstitial protein deposition were observed, peaking on days 7 and 28, respectively. Interstitial infiltrates of BMDC and myofibroblasts reached a maximum on day 7 and gradually decreased afterward. Over time, an average of 32% of all interstitial alpha-smooth muscle actin-positive myofibroblasts coexpressed R26-human placental alkaline phosphatase and, therefore, were derived from the BM. BMD myofibroblasts produced procollagen I protein and therefore were functional. The postischemic kidney environment was profibrotic, as demonstrated by increased transcription of TGF-beta and decreased transcription of bone morphogenic protein-7. TGF-beta protein was present predominantly in interstitial myofibroblasts but not in BMD myofibroblasts. In conclusion, functional BMD myofibroblasts infiltrate in the postischemic renal interstitium and are involved in extracellular matrix production.


Asunto(s)
Colágeno Tipo I/biosíntesis , Riñón/lesiones , Animales , Animales Modificados Genéticamente , Trasplante de Médula Ósea , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Creatinina/sangre , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Riñón/metabolismo , Riñón/patología , Masculino , ARN/genética , ARN/metabolismo , Ratas , Ratas Endogámicas F344 , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Daño por Reperfusión/cirugía , Factor de Crecimiento Transformador beta/metabolismo , Quimera por Trasplante
9.
Kidney Int ; 68(6): 2572-81, 2005 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16316332

RESUMEN

BACKGROUND: Ischemia/reperfusion (I/R) injury is a major cause of acute renal failure (ARF). ARF is reversible, due to an innate regenerative process, which is thought to depend partly on bone marrow-derived progenitor cells. The significance of these cells in the repair process has been questioned in view of their relatively low frequency. Here, we hypothesize that the severity of renal damage and the postischemic recovery time are determinants of tubular bone marrow-derived cell (BMDC) engraftment. METHODS: We used a model of unilateral renal I/R in F344 rats reconstituted with R26-human placental alkaline phosphatase (hPAP) transgenic bone marrow, in which we quantified and characterized tubular BMDC engraftment with increasing severity of damage and in time. RESULTS: After I/R injury, BMDC engrafted the tubular epithelium and acquired an epithelial phenotype. Tubular epithelial BMDC engraftment increased with longer ischemic time, indicating that tubular epithelial BMDC engraftment increases with the severity of damage. The number of circulating progenitor cells doubled early after I/R injury and was followed by a transient increase in tubular epithelial BMDC engraftment. The latter positively correlated with morphological recovery of the kidney over time. CONCLUSION. The extent of tubular BMDC engraftment depends on the severity of renal damage and follows a distinct time course after I/R injury. Therefore, the severity of damage and time course need to be taken into account when interpreting data on the role of tubular BMDC engraftment in renal repair after I/R injury.


Asunto(s)
Lesión Renal Aguda/patología , Lesión Renal Aguda/terapia , Trasplante de Médula Ósea/métodos , Daño por Reperfusión/patología , Daño por Reperfusión/terapia , Animales , Antimetabolitos , Bromodesoxiuridina , Células Epiteliales/patología , Túbulos Renales/patología , Túbulos Renales/fisiología , Masculino , Ratas , Ratas Endogámicas F344 , Recuperación de la Función , Regeneración , Índice de Severidad de la Enfermedad
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