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1.
Rozhl Chir ; 98(10): 388-393, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31842567

RESUMEN

Repopulation of decellularized tissue with cells is a very promising approach in tissue engineering, with liver tissue engineering not being an exception. Decellularized liver scaffolds can serve as an excellent 3D environment for recellularization as it maintain tissue-specific microarchitecture of ECM proteins with important spatial cues for cell adhesion, migration, growth and differentiation. Moreover, by using autologous cells the newly constructed graft should lack immunogenicity in the host organism and thus eliminate the need for immunosuppressive therapy in the post-transplant period. This review provides an overview of liver decellularization and repopulation experiments done so far while highlighting the advances as well as pin-pointing the challenges that remain to be solved.


Asunto(s)
Hígado/fisiología , Ingeniería de Tejidos/métodos , Andamios del Tejido , Animales , Fenómenos Fisiológicos Celulares , Matriz Extracelular/fisiología , Humanos , Hígado/citología , Porcinos
2.
Adv Exp Med Biol ; 1190: 107-122, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31760641

RESUMEN

Enriched Na+ channel clustering allows for rapid saltatory conduction at a specialized structure in myelinated axons, the node of Ranvier, where cations are exchanged across the axon membrane. In the extracellular matrix (ECM), highly negatively charged molecules accumulate and wrap around the nodal gaps creating an ECM dome, called the perinodal ECM. The perinodal ECM has different molecular compositions in the central nervous system (CNS) and peripheral nervous system (PNS). Chondroitin sulfate proteoglycans are abundant in the ECM at the CNS nodes, whereas heparan sulfate proteoglycans are abundant at the PNS nodes. The proteoglycans have glycosaminoglycan chains on their core proteins, which makes them electrostatically negative. They associate with other ECM molecules and form a huge stable ECM complex at the nodal gaps. The polyanionic molecular complexes have high affinity to cations and potentially contribute to preventing cation diffusion at the nodes.In this chapter, we describe the molecular composition of the perinodal ECM in the CNS and PNS, and discuss their physiological role at the node of Ranvier.


Asunto(s)
Sistema Nervioso Central/fisiología , Matriz Extracelular/fisiología , Sistema Nervioso Periférico/fisiología , Nódulos de Ranvier/fisiología , Axones/fisiología , Sulfatos de Condroitina/fisiología , Glicosaminoglicanos/fisiología , Heparitina Sulfato/fisiología , Humanos , Proteoglicanos/fisiología
3.
Life Sci ; 239: 117049, 2019 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-31730862

RESUMEN

Cancer associated fibroblasts (CAFs) as the dominant, long-lived and highly plastic cells within the tumor microenvironment (TME) with multi-faceted roles that are endowed with tumor aggressive features. They can instruct and shape the stroma of tumor into being a highly qualified bed for cellular recruitment, differentiation and plasticity in the host tissue or secondary organ/s. In this Review, we have a discussion over CAF reprogramming as a general concept, inducers and outcomes, pursued by suggesting potential strategies to combat this key promoter of tumor.


Asunto(s)
Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/fisiología , Reprogramación Celular/fisiología , Matriz Extracelular/metabolismo , Matriz Extracelular/fisiología , Fibroblastos/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Neoplasias/patología , Células del Estroma/metabolismo , Factores de Crecimiento Transformadores/metabolismo , Factores de Crecimiento Transformadores/fisiología , Microambiente Tumoral
4.
Nat Protoc ; 14(12): 3395-3425, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31705125

RESUMEN

The extracellular matrix (ECM) is a major regulator of homeostasis and disease, yet the 3D structure of the ECM remains poorly understood because of limitations in ECM visualization. We recently developed an ECM-specialized method termed in situ decellularization of tissues (ISDoT) to isolate native 3D ECM scaffolds from whole organs in which ECM structure and composition are preserved. Here, we present detailed surgical instructions to facilitate decellularization of 33 different mouse tissues and details of validated antibodies that enable the visualization of 35 mouse ECM proteins. Through mapping of these ECM proteins, the structure of the ECM can be determined and tissue structures visualized in detail. In this study, perfusion decellularization is presented for bones, skeletal muscle, tongue, salivary glands, stomach, duodenum, jejunum/ileum, large intestines, mesentery, liver, gallbladder, pancreas, trachea, bronchi, lungs, kidneys, urinary bladder, ovaries, uterine horn, cervix, adrenal gland, heart, arteries, veins, capillaries, lymph nodes, spleen, peripheral nerves, eye, outer ear, mammary glands, skin, and subcutaneous tissue. Decellularization, immunostaining, and imaging take 4-5 d.


Asunto(s)
Matriz Extracelular/metabolismo , Imagen Tridimensional/métodos , Coloración y Etiquetado/métodos , Animales , Anticuerpos/metabolismo , Matriz Extracelular/fisiología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Especificidad de Órganos , Perfusión/métodos , Ingeniería de Tejidos/métodos , Andamios del Tejido/química
5.
PLoS Comput Biol ; 15(10): e1007251, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31658254

RESUMEN

The higher-order patterning of extra-cellular matrix in normal and pathological tissues has profound consequences on tissue function. Whilst studies have documented both how fibroblasts create and maintain individual matrix fibers and how cell migration is altered by the fibers they interact with, a model unifying these two aspects of tissue organization is lacking. Here we use computational modelling to understand the effect of this interconnectivity between fibroblasts and matrix at the mesoscale level. We created a unique adaptation to the Vicsek flocking model to include feedback from a second layer representing the matrix, and use experimentation to parameterize our model and validate model-driven hypotheses. Our two-layer model demonstrates that feedback between fibroblasts and matrix increases matrix diversity creating higher-order patterns. The model can quantitatively recapitulate matrix patterns of tissues in vivo. Cells follow matrix fibers irrespective of when the matrix fibers were deposited, resulting in feedback with the matrix acting as temporal 'memory' to collective behaviour, which creates diversity in topology. We also establish conditions under which matrix can be remodelled from one pattern to another. Our model elucidates how simple rules defining fibroblast-matrix interactions are sufficient to generate complex tissue patterns.


Asunto(s)
Biología Computacional/métodos , Matriz Extracelular/fisiología , Fibroblastos/fisiología , Animales , Comunicación Celular/fisiología , Movimiento Celular/fisiología , Células Cultivadas , Simulación por Computador , Retroalimentación , Humanos , Ratones , Programas Informáticos
6.
J Appl Oral Sci ; 27: e20180596, 2019 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-31508793

RESUMEN

Bone development and healing processes involve a complex cascade of biological events requiring well-orchestrated synergism with bone cells, growth factors, and other trophic signaling molecules and cellular structures. Beyond health processes, MMPs play several key roles in the installation of heart and blood vessel related diseases and cancer, ranging from accelerating metastatic cells to ectopic vascular mineralization by smooth muscle cells in complementary manner. The tissue inhibitors of MMPs (TIMPs) have an important role in controlling proteolysis. Paired with the post-transcriptional efficiency of specific miRNAs, they modulate MMP performance. If druggable, these molecules are suggested to be a platform for development of "smart" medications and further clinical trials. Thus, considering the pleiotropic effect of MMPs on mammals, the purpose of this review is to update the role of those multifaceted proteases in mineralized tissues in health, such as bone, and pathophysiological disorders, such as ectopic vascular calcification and cancer.


Asunto(s)
Remodelación Ósea/fisiología , Matriz Extracelular/fisiología , Metaloproteinasas de la Matriz/fisiología , Enfermedades Óseas/metabolismo , Enfermedades Óseas/fisiopatología , Progresión de la Enfermedad , Humanos , Inhibidores de la Metaloproteinasa de la Matriz/uso terapéutico , Neoplasias/metabolismo , Neoplasias/fisiopatología , Osteoblastos/fisiología , Inhibidores Tisulares de Metaloproteinasas/fisiología , Calcificación Vascular/metabolismo , Calcificación Vascular/fisiopatología
7.
Elife ; 82019 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-31535975

RESUMEN

Changes in cell proliferation define transitions from tissue growth to physiological homeostasis. In tendons, a highly organized extracellular matrix undergoes significant postnatal expansion to drive growth, but once formed, it appears to undergo little turnover. However, tendon cell activity during growth and homeostatic maintenance is less well defined. Using complementary methods of genetic H2B-GFP pulse-chase labeling and BrdU incorporation in mice, we show significant postnatal tendon cell proliferation, correlating with longitudinal Achilles tendon growth. Around day 21, there is a transition in cell turnover with a significant decline in proliferation. After this time, we find low amounts of homeostatic tendon cell proliferation from 3 to 20 months. These results demonstrate that tendons harbor significant postnatal mitotic activity, and limited, but detectable activity in adult and aged stages. It also points towards the possibility that the adult tendon harbors resident tendon progenitor populations, which would have important therapeutic implications.


Asunto(s)
Tendón Calcáneo/crecimiento & desarrollo , Ciclo Celular/genética , Proliferación Celular/fisiología , Homeostasis/genética , Tendón Calcáneo/fisiología , Animales , Matriz Extracelular/genética , Matriz Extracelular/fisiología , Ratones , Células Madre/metabolismo
8.
PLoS Comput Biol ; 15(9): e1006798, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31539369

RESUMEN

Cells interacting through an extracellular matrix (ECM) exhibit emergent behaviors resulting from collective intercellular interaction. In wound healing and tissue development, characteristic compaction of ECM gel is induced by multiple cells that generate tensions in the ECM fibers and coordinate their actions with other cells. Computational prediction of collective cell-ECM interaction based on first principles is highly complex especially as the number of cells increase. Here, we introduce a computationally-efficient method for predicting nonlinear behaviors of multiple cells interacting mechanically through a 3-D ECM fiber network. The key enabling technique is superposition of single cell computational models to predict multicellular behaviors. While cell-ECM interactions are highly nonlinear, they can be linearized accurately with a unique method, termed Dual-Faceted Linearization. This method recasts the original nonlinear dynamics in an augmented space where the system behaves more linearly. The independent state variables are augmented by combining auxiliary variables that inform nonlinear elements involved in the system. This computational method involves a) expressing the original nonlinear state equations with two sets of linear dynamic equations b) reducing the order of the augmented linear system via principal component analysis and c) superposing individual single cell-ECM dynamics to predict collective behaviors of multiple cells. The method is computationally efficient compared to original nonlinear dynamic simulation and accurate compared to traditional Taylor expansion linearization. Furthermore, we reproduce reported experimental results of multi-cell induced ECM compaction.


Asunto(s)
Fenómenos Fisiológicos Celulares/fisiología , Matriz Extracelular/fisiología , Modelos Biológicos , Fenómenos Biomecánicos/fisiología , Módulo de Elasticidad/fisiología , Dinámicas no Lineales , Seudópodos/fisiología
9.
Biomed Pharmacother ; 117: 109146, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31387186

RESUMEN

Mesenchymal stem cells and chondrocytes are an important source of the cells for cartilage tissue engineering. Therefore, the culture and expansion methods of these cells need to be improved to overcome the aging of chondrocytes and induced chondrogenic differentiation of mesenchymal stem cells. The aim of this study was to expand the cells for cartilage tissue engineering by combining the advantages of growing cells in co-culture and under a mechanically-stimulated environment. Rabbit chondrocytes and co-cultured cells (bone mesenchymal stem cells and chondrocytes) were subjected to cyclic sinusoidal dynamic tensile mechanical stimulationusing the FX-4000 tension system. Chondrocyte proliferation was assayed by flow cytometry and CFSE labeling. The cell cartilage phenotype was determined by detecting GAG, collagen II and TGF-ß1 protein expression by ELISA and the Col2α1, TGF-ß1 and Sox9 gene expression by RT-PCR. The results show that the co-culture improved both the proliferation ability of chondrocytes and the cartilage phenotype of co-cultured cells. A proper cyclic sinusoidal dynamic tensile mechanical stimulation improved the proliferation ability and cartilage phenotype of chondrocytes and co-cultured cells. These results suggest that the co-culture of mesenchymal stem cells with chondrocytes and proper mechanical stimulation may be an appropriate way to rapidly expand the cells that have an improved cartilage phenotype for cartilage tissue engineering.


Asunto(s)
Cartílago/fisiología , Proliferación Celular/fisiología , Condrocitos/fisiología , Células Madre Mesenquimatosas/fisiología , Animales , Cartílago/metabolismo , Diferenciación Celular/fisiología , Células Cultivadas , Condrocitos/metabolismo , Condrogénesis/fisiología , Técnicas de Cocultivo/métodos , Colágeno Tipo II/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/fisiología , Células Madre Mesenquimatosas/metabolismo , Fenotipo , Conejos , Factor de Transcripción SOX9/metabolismo , Ingeniería de Tejidos/métodos , Factor de Crecimiento Transformador beta1/metabolismo
10.
Br J Radiol ; 92(1103): 20190443, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31433668

RESUMEN

MRI of articular cartilage (AC) integrity has potential to become a biomarker for osteoarthritis progression. Traditional MRI sequences evaluate AC morphology, allowing for the measurement of thickness and its change over time. In the last two decades, more advanced, dedicated MRI cartilage sequences have been developed aiming to assess AC matrix composition non-invasively and detect early changes in cartilage not captured on morphological sequences. T2-mapping and T1ρ sequences can be used to estimate the relaxation times of water inside the AC. These sequences have been introduced into clinical protocols and show promising results for cartilage assessment. Extracelullar matrix can also be assessed using diffusion-weighted imaging and diffusion tensor imaging as the movement of water is limited by the presence of extracellular matrix in AC. Specific techniques for glycosaminoglycans (GAG) evaluation, such as delayed gadolinium enhanced MRI of cartilage or Chemical Exchange Saturation Transfer imaging of GAG, as well as sodium imaging have also shown utility in the detection of AC damage. This manuscript provides an educational update on the physical principles behind advanced AC MRI techniques as well as a comprehensive review of the strengths and weaknesses of each approach. Current clinical applications and potential future applications of these techniques are also discussed.


Asunto(s)
Cartílago Articular/fisiología , Matriz Extracelular/fisiología , Imagen por Resonancia Magnética/métodos , Medios de Contraste , Gadolinio , Glicosaminoglicanos/metabolismo , Humanos , Imagen por Resonancia Magnética/normas , Pronóstico , Sensibilidad y Especificidad , Sodio
11.
Mol Biol Rep ; 46(4): 4369-4375, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31267326

RESUMEN

Therapeutic benefits of deep brain stimulation (DBS), a neurosurgical treatment for certain movement disorders and other neurologic conditions, are well documented, but DBS mechanisms remain largely unexplained. DBS is thought to modulate pathological neural activity. However, although astrocytes, the most numerous cell type in the brain, play a significant role in neurotransmission, chemical homeostasis and synaptic plasticity, their role in DBS has not been fully examined. To investigate astrocytic function in DBS, we applied DBS-like high frequency electrical stimulation for 24 h to human astrocytes in vitro and analyzed single cell transcriptome mRNA profile. We found that DBS-like high frequency stimulation negatively impacts astrocyte metabolism and promotes the release of extracellular matrix (matricellular) proteins, including IGFBP3, GREM1, IGFBP5, THBS1, and PAPPA. Our results suggest that astrocytes are involved in the long-term modulation of extra cellular matrix environments and that they may influence persistent cell-to-cell interaction and help maintain neuromodulation over time.


Asunto(s)
Astrocitos/metabolismo , Estimulación Encefálica Profunda/métodos , Proteínas de la Matriz Extracelular/metabolismo , Astrocitos/fisiología , Encéfalo , Estimulación Eléctrica/métodos , Matriz Extracelular/metabolismo , Matriz Extracelular/fisiología , Expresión Génica/genética , Humanos , Plasticidad Neuronal , Cultivo Primario de Células , Análisis de Secuencia de ARN/métodos , Análisis de la Célula Individual
12.
ACS Appl Mater Interfaces ; 11(30): 26559-26570, 2019 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-31267742

RESUMEN

Recently, the scientific community has shown considerable interest in engineering tissues with organized compositional and structural gradients to mimic hard-to-soft tissue interfaces. This effort is hindered by an incomplete understanding of the construction of native tissue interfaces. In this work, we combined Raman microscopy and confocal elastography to map compositional, structural, and mechanical features across the stiff-to-compliant interface of the attachments of the meniscus in the knee. This study provides new insight into the methods by which biology mediates multiple orders of magnitude changes in stiffness over tens of microns. We identified how the nano- to mesoscale architecture mediates complex microscale transitional regions across the interface: two regions defined by chemical composition, five distinguished by structural features, and three mechanically distinct regions. We identified three major components that lead to a robust interface between a soft tissue and bone: mobile collagen fiber units, a continuous interfacial region, and a local stiffness gradient. This tissue architecture allows for large displacements of collagen fibers in the attachments, enabling meniscal movement without localizing strains to the soft tissue-to-bone interface. The interplay of these regions reveals a method relying on hierarchical structuring across multiple length scales to minimize stress concentrators between highly dissimilar materials. These insights inspire new design strategies for synthetic soft tissue-to-bone attachments and biomimetic material interfaces.


Asunto(s)
Materiales Biomiméticos/uso terapéutico , Articulación de la Rodilla/fisiología , Menisco/fisiología , Tendones/fisiología , Huesos/fisiología , Matriz Extracelular/fisiología , Humanos , Ingeniería de Tejidos , Andamios del Tejido
13.
Endocrinology ; 160(8): 1885-1894, 2019 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-31271410

RESUMEN

This review describes formation of the islet basement membrane and the function of extracellular matrix (ECM) components in ß-cell proliferation and survival. Implications for islet transplantation are discussed. The insulin-producing ß-cell is key for maintaining glucose homeostasis. The islet microenvironment greatly influences ß-cell survival and proliferation. Within the islet, ß-cells contact the ECM, which is deposited primarily by intraislet endothelial cells, and this interaction has been shown to modulate proliferation and survival. ECM-localized growth factors, such as vascular endothelial growth factor and cellular communication network 2, signal through specific receptors and integrins on the ß-cell surface. Further understanding of how the ECM functions to influence ß-cell proliferation and survival will provide targets for enhancing functional ß-cell mass for the treatment of diabetes.


Asunto(s)
Matriz Extracelular/fisiología , Células Secretoras de Insulina/fisiología , Animales , Proliferación Celular , Supervivencia Celular , Colágeno/fisiología , Factor de Crecimiento del Tejido Conjuntivo/fisiología , Humanos , Integrinas/fisiología , Factor A de Crecimiento Endotelial Vascular/fisiología
14.
Int J Artif Organs ; 42(12): 757-764, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31328608

RESUMEN

Despite remarkable advancement in the past decades, heart-related defects are still prone to progress irreversibly and can eventually lead to heart failure. A personalized extracellular matrix-based bioartificial heart created by allografts/xenografts emerges as an alternative as it can retain the original three-dimensional architecture combined with a preserved natural heart extracellular matrix. This study aimed at developing a procedure for decellularizing heart tissue harvested from rats and evaluating decellularization efficiency in terms of residual nuclear content and structural properties. Tissue sections showed no or little visible cell nuclei in decellularized heart, whereas the native heart showed dense cellularity. In addition, there was no significant variation in the alignment of muscle fibers upon decellularization. Furthermore, no significant difference was detected between native and decellularized hearts in terms of fiber diameter. Our findings demonstrate that fiber alignment and diameter can serve as additional parameters in the characterization of biological heart scaffolds as these provide valuable input for evaluating structural preservation of decellularized heart. The bioartificial scaffold formed here can be functionalized with patient's own material and utilized in regenerative engineering.


Asunto(s)
Matriz Extracelular/fisiología , Miocardio/citología , Ingeniería de Tejidos/métodos , Andamios del Tejido , Animales , Materiales Biocompatibles , Corazón , Corazón Artificial , Humanos , Masculino , Ensayo de Materiales/métodos , Perfusión , Ratas
15.
Arterioscler Thromb Vasc Biol ; 39(7): 1432-1447, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31242033

RESUMEN

Objective- The Wnt/ß-catenin pathway orchestrates development of the blood-brain barrier, but the downstream mechanisms involved at different developmental windows and in different central nervous system (CNS) tissues have remained elusive. Approach and Results- Here, we create a new mouse model allowing spatiotemporal investigations of Wnt/ß-catenin signaling by induced overexpression of Axin1, an inhibitor of ß-catenin signaling, specifically in endothelial cells ( Axin1 iEC- OE). AOE (Axin1 overexpression) in Axin1 iEC- OE mice at stages following the initial vascular invasion of the CNS did not impair angiogenesis but led to premature vascular regression followed by progressive dilation and inhibition of vascular maturation resulting in forebrain-specific hemorrhage 4 days post-AOE. Analysis of the temporal Wnt/ß-catenin driven CNS vascular development in zebrafish also suggested that Axin1 iEC- OE led to CNS vascular regression and impaired maturation but not inhibition of ongoing angiogenesis within the CNS. Transcriptomic profiling of isolated, ß-catenin signaling-deficient endothelial cells during early blood-brain barrier-development (E11.5) revealed ECM (extracellular matrix) proteins as one of the most severely deregulated clusters. Among the 20 genes constituting the forebrain endothelial cell-specific response signature, 8 ( Adamtsl2, Apod, Ctsw, Htra3, Pglyrp1, Spock2, Ttyh2, and Wfdc1) encoded bona fide ECM proteins. This specific ß-catenin-responsive ECM signature was also repressed in Axin1 iEC- OE and endothelial cell-specific ß-catenin-knockout mice ( Ctnnb1-KOiEC) during initial blood-brain barrier maturation (E14.5), consistent with an important role of Wnt/ß-catenin signaling in orchestrating the development of the forebrain vascular ECM. Conclusions- These results suggest a novel mechanism of establishing a CNS endothelium-specific ECM signature downstream of Wnt-ß-catenin that impact spatiotemporally on blood-brain barrier differentiation during forebrain vessel development. Visual Overview- An online visual overview is available for this article.


Asunto(s)
Matriz Extracelular/fisiología , Prosencéfalo/irrigación sanguínea , Vía de Señalización Wnt/fisiología , beta Catenina/fisiología , Animales , Proteína Axina/fisiología , Barrera Hematoencefálica , Masculino , Ratones , Ratones Endogámicos C57BL , Transducción de Señal/fisiología , Remodelación Vascular , Pez Cebra
16.
J Biol Regul Homeost Agents ; 33(2 Suppl. 1): 119-124, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31169013

RESUMEN

Menisci act like shock absorbers and transmit load across the tibiofemoral joint by increasing congruency during movements or body weight load. This leads to decreasing the resultant stress on the articular cartilages. The meniscus has a dense extracellular matrix (ECM) composed of water, different types of collagens, and proteoglycans, such as decorin, aggrecan and biglycan. Decorin (DCN) regulates collagen fibrillogenesis acting on collagen fibrils diameter and fibrils orientation to achieve the proper assembly of its network. This work investigates the spatial disposition of this fundamental protein in pig meniscus' matrix by immunohistochemistry and western blot analysis. DCN shows an increasing trend, moving from neonatal to adult pig menisci. Adult meniscus, in porcine species, is the only one that could be considered fully mature and functional, and, even if an increasing trend is seen, no precise phenotypical switch points are seen in the age stages considered in this study.


Asunto(s)
Factores de Edad , Decorina/fisiología , Matriz Extracelular/fisiología , Menisco/fisiología , Animales , Porcinos
17.
Nat Rev Cardiol ; 16(12): 727-744, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31243391

RESUMEN

Vascular smooth muscle cells (VSMCs) are a major cell type present at all stages of an atherosclerotic plaque. According to the 'response to injury' and 'vulnerable plaque' hypotheses, contractile VSMCs recruited from the media undergo phenotypic conversion to proliferative synthetic cells that generate extracellular matrix to form the fibrous cap and hence stabilize plaques. However, lineage-tracing studies have highlighted flaws in the interpretation of former studies, revealing that these studies had underestimated both the content and functions of VSMCs in plaques and have thus challenged our view on the role of VSMCs in atherosclerosis. VSMCs are more plastic than previously recognized and can adopt alternative phenotypes, including phenotypes resembling foam cells, macrophages, mesenchymal stem cells and osteochondrogenic cells, which could contribute both positively and negatively to disease progression. In this Review, we present the evidence for VSMC plasticity and summarize the roles of VSMCs and VSMC-derived cells in atherosclerotic plaque development and progression. Correct attribution and spatiotemporal resolution of clinically beneficial and detrimental processes will underpin the success of any therapeutic intervention aimed at VSMCs and their derivatives.


Asunto(s)
Aterosclerosis/patología , Miocitos del Músculo Liso/patología , Animales , Plasticidad de la Célula , Proliferación Celular , Senescencia Celular , Progresión de la Enfermedad , Matriz Extracelular/fisiología , Humanos , Miocitos del Músculo Liso/fisiología , Fenotipo , Placa Aterosclerótica/patología
18.
Exp Eye Res ; 182: 182-193, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30953624

RESUMEN

This paper aims to identify key biological processes triggered by resection surgery in the extraocular muscles (EOMs) of a rabbit model of strabismus surgery by studying changes in gene expression. Resection surgery was performed in the superior rectus of 16 rabbits and a group of non-operated rabbits served as control. Muscle samples were collected from groups of four animals 1, 2, 4 and 6 weeks after surgery and processed for RNA-sequencing and immunohistochemistry. We identified a total of 164; 136; 64 and 12 differentially expressed genes 1, 2, 4 and 6 weeks after surgery. Gene Ontology enrichment analysis revealed that differentially expressed genes were involved in biological pathways related to metabolism, response to stimulus mainly related with regulation of immune response, cell cycle and extracellular matrix. A complementary pathway analysis and network analysis performed with Ingenuity Pathway Analysis tool corroborated and completed these findings. Collagen I, fibronectin and versican, evaluated by immunofluorescence, showed that changes at the gene expression level resulted in variation at the protein level. Tenascin-C staining in resected muscles demonstrated the formation of new tendon and myotendinous junctions. These data provide new insights about the biological response of the EOMs to resection surgery and may form the basis for future strategies to improve the outcome of strabismus surgery.


Asunto(s)
Músculos Oculomotores/metabolismo , Estrabismo/metabolismo , Estrabismo/cirugía , Animales , Ciclo Celular/fisiología , Modelos Animales de Enfermedad , Matriz Extracelular/fisiología , Perfilación de la Expresión Génica , Inmunidad Innata/fisiología , Conejos
19.
PLoS Comput Biol ; 15(4): e1006684, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30958816

RESUMEN

The mechanical properties of the extracellular matrix (ECM)-a complex, 3D, fibrillar scaffold of cells in physiological environments-modulate cell behavior and can drive tissue morphogenesis, regeneration, and disease progression. For simplicity, it is often convenient to assume these properties to be time-invariant. In living systems, however, cells dynamically remodel the ECM and create time-dependent local microenvironments. Here, we show how cell-generated contractile forces produce substantial irreversible changes to the density and architecture of physiologically relevant ECMs-collagen I and fibrin-in a matter of minutes. We measure the 3D deformation profiles of the ECM surrounding cancer and endothelial cells during stages when force generation is active or inactive. We further correlate these ECM measurements to both discrete fiber simulations that incorporate fiber crosslink unbinding kinetics and continuum-scale simulations that account for viscoplastic and damage features. Our findings further confirm that plasticity, as a mechanical law to capture remodeling in these networks, is fundamentally tied to material damage via force-driven unbinding of fiber crosslinks. These results characterize in a multiscale manner the dynamic nature of the mechanical environment of physiologically mimicking cell-in-gel systems.


Asunto(s)
Matriz Extracelular/fisiología , Seudópodos/fisiología , Fenómenos Biomecánicos , Biopolímeros/química , Biopolímeros/fisiología , Línea Celular , Microambiente Celular/fisiología , Biología Computacional , Simulación por Computador , Matriz Extracelular/química , Matriz Extracelular/ultraestructura , Células Endoteliales de la Vena Umbilical Humana , Humanos , Imagen Tridimensional , Cinética , Modelos Biológicos , Seudópodos/química , Seudópodos/ultraestructura
20.
Nat Commun ; 10(1): 1592, 2019 04 08.
Artículo en Inglés | MEDLINE | ID: mdl-30962434

RESUMEN

Regeneration and tissue turnover require new cell production and positional information. Planarians are flatworms capable of regenerating all body parts using a population of stem cells called neoblasts. The positional information required for tissue patterning is primarily harbored by muscle cells, which also control body contraction. Here we produce an in silico planarian matrisome and use recent whole-animal single-cell-transcriptome data to determine that muscle is a major source of extracellular matrix (ECM). No other ECM-secreting, fibroblast-like cell type was detected. Instead, muscle cells express core ECM components, including all 19 collagen-encoding genes. Inhibition of muscle-expressed hemicentin-1 (hmcn-1), which encodes a highly conserved ECM glycoprotein, results in ectopic peripheral localization of cells, including neoblasts, outside of the muscle layer. ECM secretion and hmcn-1-dependent maintenance of tissue separation indicate that muscle functions as a planarian connective tissue, raising the possibility of broad roles for connective tissue in adult positional information.


Asunto(s)
Tejido Conectivo/fisiología , Matriz Extracelular/fisiología , Fenómenos Fisiológicos Musculoesqueléticos , Planarias/fisiología , Animales , Células del Tejido Conectivo/fisiología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Ratones , Células Musculares/fisiología , Planarias/genética , Dominios Proteicos , Proteínas/química , Proteínas/genética , Proteínas/metabolismo , Interferencia de ARN
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