GAGs are unbranched chains of polysaccharides; GAGs are composed of repeating disaccharide units and are heterogeneous groups in negatively charged polysaccharide chains that are covalently linked to proteins to form proteoglycan molecules. The name GAGs is because in this polysaccharide, one of the two sugars in a repetitive disaccharide is always an amino sugar such as N-acetylglucosamine or N-acetylgalactosamine [ 3 ].
The second sugar of GAGs usually is the uronic acid like glucuronic or iduronate. GAG molecules are negatively charged, because there are sulfate or carboxyl groups in most of the sugar. The five main groups of GAGs are differentiated based on the sugar type including 1 hyaluronan or hyaluronic acid, 2 chondroitin sulfate, 3 dermatan sulfate, 4 heparan sulfate, and 5 keratin sulfate. Hyaluronan is the simplest GAGs. Hyaluronan does not contain sulfate sugars; all disaccharides units are the same, and the chain length is extensively big thousands of sugar monomers.
The hyaluronan is not connected covalently to some core proteins. Proteoglycans are composed of GAG chains that are covalently linked to the core protein and considered to have a significant role in chemical signaling among cells Figure 4. The structure of glycosaminoglycan A structure of a proteoglycan monomer. Several glycosaminoglycan chains chondroitin sulfphate and keratan sulfate attached to a core protein. The protein molecule can connect to a long hyaluronic acid molecule to help form a proteoglycan aggregate.
B An example of an individual glycosaminoglycan chain, in this case, chondroitin 6-sulphate, and its attachment to the core protein. C The morphological of a proteoglycan monomer. Collagen is a major abundant fibrous protein in the extracellular matrix. Collagens, which constitute the primary structural element of the ECM, provide tensile strength, regulate cell adhesion, support chemotaxis and migration, and direct tissue development [ 4 ].
Recently, there have been already described 28 types of collagen. After secretion, the fibrillar procollagen molecule divides to become collagen molecules, which converge into fibrils [ 5 ]. Fibronectin is an extracellular protein that makes cells adhere to the matrix.
Fibronectin is considered as a large glycoprotein found in all vertebrates. Fibronectin is a ligand member of the integrin receptor family. Integrins are structurally and functionally related to the cell surface as heterodimeric receptors that link the ECM with the intracellular cytoskeleton.
The primary type of fibronectin is known as type III fibronectin replica cylinder , which binds to integrins. This model has a length of about 90 amino acids. Fibronectin appears in a soluble and fibrillar form. There are two others fibronectin isoforms, which are fibronectin type I hexagon and fibronectin type II square [ 6 ]. Fibronectin is not only crucial for attaching cells to matrices but also to guiding cell migration in vertebrate embryos.
Fibronectin has many functions, which allow it to interact with many extracellular substances, such as collagen, fibrin and heparin, and with specific membrane receptors in responsive cells. Extracellular matrix is the primary factor required in the process of forming a new network and tissue. Along with the development found, many different factors can trigger the growth of ECM or used to create a synthetic ECM. The process of wound healing is strongly influenced by the role of migration and proliferation of fibroblasts in the injury site.
Indeed fibroblast is one part of ECM. The proliferation of fibroblasts determines the outcome of wound healing. Fibroblasts will produce collagen that will link to the wound, and fibroblasts will also affect the process of reepithelialization that will close the wound.
Fibroblasts will produce type III collagen during proliferation and facilitate wound closure. During proliferation stage, fibroblasts proliferation activity is higher due to the presence of TGF-stimulated fibroblasts to secrete bFGF. The higher number of fibroblasts also induces increasing of collagen synthesis.
Collagen fiber is the major protein secreted by fibroblast, composed of extracellular matrix to replace wound tissue strength and function. Collagen fibers deposition was significant on 8—10 days after injury. The number of fibroblasts increases significantly, in correlation with the presence of an abundance of bFGF on 8—10 days after wounding.
Mesenchymal stem cell conditioned medium MSCM can be defined as secreted factor that referred to as secretome, microvesicle, or exosome without the stem cells which may found in the medium where the stem cells are growing.
The use of MSCM as cell-free therapy has more significant advantages in comparison to the use of stem cells, mainly to avoid the need of HLA matching between donor and recipient as a consequence to decrease the chance of transplant rejection.
Additionally, MSCM is more easy to produce and save in large quantity. Recently, it has been mentioned that widespread neuronal cell death in the neocortex and hippocampus is an ineluctable concomitant of brain aging caused by diseases and injuries.
However, recent studies suggest that neuron death also occurs in functional aging and it seems in related to an impairment of neocortical and hippocampal functions during aging processes. Data from WHO and Alzheimer report show increasing number of people suffering from dementia along with aging.
Profoundly understanding the role of extracellular matrix ECM in influencing neurogenesis has presented novel strategies for tissue regeneration Figure 5. Microscopic anatomy of the extracellular matrix within the central nervous system CNS. The three major compartments of the extracellular matrix in the CNS are the basement membrane, perineuronal net, and neuronal interstitial matrix. The basement membrane is found surrounding cerebral blood vessels, the perineuronal net is a dense matrix immediately surrounding neuronal cell bodies and dendrites, and the neuronal interstitial matrix occupies the space between neurons and glial cells.
Adapted from Lau et al. Within this glial scar, upregulated proteoglycans like CSPGs and changes in sulfation patterns within the ECM result in the building of regeneration inhibition [ 10 ]. To solve the problem, some manipulation on the intrinsic extracellular matrix by using traditional herb such as Ocimum sanctum extract was already done. In the in vivo and in vitro model using human brain microvascular endothelial cells HBMECs which mimics blood-brain barrier, the treatment of the extract may promote the cell proliferation on the hippocampus area and HBMECs in the condition upregulation of choline acetyltransferase ChAT enzyme [ 11 , 12 ].
In addition, there is also a chance to use nanometer-sized scaffolds in the presence of other substrates such as vascular endothelial growth factor or hyaluronic acid with laminin. This scaffold may conduct a way to the regenerative capacity and functional recovery of the CNS to reconstruct formed cavities and reconnect neuronal processes.
Thus, the artificial scaffold functions to enhance the communication between cells, allowing for improvement in proliferation, migration, and differentiation [ 13 , 14 , 15 ]. In addition, on the peripheral nerve injury, there is a chance to use scaffold by a chemical decellularization process, acellular nerve allografting that eliminates the antigens responsible for allograft rejection and maintains most of the ECM components, which can effectively guide and enhance nerve regeneration.
In the field of tissue engineering by an in vivo model, a lot of successful carriers and matrices have been employed as a scaffold to promote direct axonal growth on peripheral nerve injury [ 16 ]. In conclusion, the extracellular matrix is the primary factor required in the process of forming a new network and tissue.
Along with the development found, many different factors that can trigger the growth of ECM are used to create a synthetic ECM. Recently, ECM is involved in various mechanisms such as wound healing with or without the involvement of mesenchymal conditioned medium and neuronal regeneration capability associated with pathologic and or neurodegenerative disease.
In addition, on the peripheral nerve injury, there is a chance to use scaffold by a chemical decellularization process, acellular nerve allografting to eliminate the antigens responsible for allograft rejection and maintain most of the ECM components, which can effectively guide and enhance nerve regeneration.
In the field of tissue engineering by an in vivo model, significant progress on matrices development have been utilized as a scaffold to promote direct axonal growth on peripheral nerve injury.
Interestingly, both in plant and animal systems, ECM can be strongly remodeled during virus infection, and the understanding of remodeling mechanisms and molecular players offers new perspectives for therapeutic intervention.
This review focuses on the different roles played by the ECM in plant and animal hosts during virus infection with special emphasis on the similarities and differences. Possible biotechnological applications aimed at improving viral resistance are discussed. The collection of extracellular molecules secreted by animal and plant cells is named Extracellular Matrix ECM.
ECM is generally composed of well-organized networks of polysaccharides and proteins, which play important functions in different tissues. It supports the cells in a tissue and regulates intercellular adhesion and communication. ECM serves as physical scaffold to the cell but it is also a dynamic structure remodeled by physiological cell conditions including homeostasis, survival, growth, migration and differentiation, as well as in response to diseases Bellincampi et al.
With the exception of animal and protozoal, the majority of cell types are covered by a cell wall CW , a complex network of proteins and carbohydrates, in which phenolic compounds can also be deposited during particular physiological processes Keegstra, ; Bellincampi et al. The name CW describes the characteristics of rigidity, support, and actual shape conferred by this particular ECM to plant cells Guerriero et al.
Besides the structural functions, plant CWs play critical physiological roles, among which build turgor pressure, control intercellular communication and defense response against pests and pathogens Lionetti and Metraux, ; Lionetti et al. More recently, strong evidence depicts the plant CW as a dynamic structure, largely remodeled to solve new physiological functions Ebine and Ueda, ; Lionetti et al.
Viruses are obligate intracellular parasites that do not possess the molecular machinery to replicate without a host. They need to enter host living cells and get in contact with the cytoplasm Dimitrov, The earliest and most important stage of virus infection is cell entry and the consequent transfer of viral genetic material Smith and Helenius, ; Alsteens et al.
Plant CW represents a physical barrier to viral entry and adds a higher level of difficulty to intercellular movement of viruses Lionetti et al. A contrasting situation applies to ECM of animal cells whose components can act as viral receptors favoring viral recognition, attachment and entry into the cell. Important constituents of the animal ECMs are proteoglycans PGs formed by a core protein onto which one or more glycosaminoglycans GAGs chains are covalently linked Frantz et al.
ECMs are also enriched in proteins such as collagens the main structural protein in connective tissue , elastin, fibronectin, laminins and glycoproteins. Unique among GAGs, HA is biosynthesized at the cell membrane rather than at the Golgi apparatus, is non-sulfated and not linked to proteins. Different cell types synthesize and secrete matrix macromolecules under the control of multiple signals.
Variations in the composition and structure of ECM, that can be endogenously mediated by proteinases, such as the Matrix Metallo Proteinases MMPs , affect both the overall structure and biomechanical properties of the formed network, but also the signals transmitted to cells, thus modulating their responses Bonnans et al.
The CW is organized into paracrystalline structures micro- and macrofibrils embedded in a rich matrix of diverse polysaccharides, including hemicelluloses and pectins, structural glycoproteins and lignin in certain tissues Zablackis et al. While cellulose is synthesized at the plasma membrane PM McNamara et al. To initiate infection, animal viruses face the extracellular matrix of animal cells before traversing the host-cell PM. ECM represents a formidable barrier but different viruses evolved specific strategies to overcome and even exploit it for cell entry.
Viral entry starts with attachment to cell-surface receptors and ends with the transfer of the viral genome to the cytoplasm Dimitrov, After recognition and binding of cell surface receptors, which can be proteins, carbohydrates or lipids, viruses can enter cells via endocytosis.
ECM appears to be involved in the attachment, the first steps of virus entry Figure 1A. The number and type of sulfation can influence virus attachments and infection Knappe et al.
The Laminin 5, a high-molecular weight protein of the extracellular matrix, shows high affinity to human papillomavirus type 11 HPV11 virions and, in addition to HS, can mediate binding to ECM Richards et al. HS and glycosphingolipids as well as carbohydrate-binding proteins like lectins, are thought to act as co-receptor molecules, which enhance the efficiency of entry of dengue virus, causing fever and hemorrhagic disorders in humans and non-human primates Hidari and Suzuki, It is hypothesized that some hepatitis C virus HCV glycoproteins attach to lectins on the host cell surface liver cells for infection Bartenschlager and Sparacio, Sialic acid-containing glycans are used by many viruses, like Influenza-, Parainfluenza-, Mumps-, Corona-, Noro-, Rotavirus, and DNA tumor viruses, as receptors for cell entry Stencel-Baerenwald et al.
Viruses can interact with secondary binding sites HSPG 2 or sialic acid-containing glycans present on the cell surface. Interaction with cell surface receptor can induce conformational triggering endocytosis. B Plant viruses can enter host cells and get in contact with the cytoplasm only via feeding of invertebrate vectors, e. Once inside the cell cytoplasm, both animal and plant viruses are uncoated and replicated following similar routes.
In plant, the CW is an effective selective filter with an exclusion limit of approximately 60 kDa that allows diffusion of water, ions and signaling molecules but excludes virus particles Tepfer and Taylor, Crossing the CW is a major challenge for viruses and such complex process is not yet fully understood.
Viruses can enter host cells and get in contact with the cytoplasm only through mechanical wounding involving partial destruction of the CW and perforation of the PM, or via feeding of invertebrate vectors such as fungi, nematodes or insects Hull, Figure 1B.
In addition, viruses can be vertically transmitted through seeds or by vegetative propagation Blanc, Once inside the plant cell cytoplasm, viruses are uncoated and replicated following features similar to those described for animal viruses. In the second half of the 20th century, a number of studies have been conducted to uncover the mechanism s of virus entry into the plant cells Shaw, Efforts made to investigate whether viruses enter plant cells via pinocytosis or attachment to specific cell-surface receptors following inoculation remained unfruitful.
Observations of tobacco mosaic virus TMV and tobacco rattle virus TRV rod-shaped particles with their ends attached to the outer CW surface or to protoplasts after manual inoculation suggested that extracellular attachment site would facilitate cell entry of virion or RNA virus genome Gaard and de Zoeten, However, virus attachment was not proved specific to susceptible hosts and no definitive evidence of virus entry upon attachment has been obtained so far.
To the best actual knowledge, plant viruses cannot actively break the CW, and while endocytosis-like pathways have been observed in plants Kitakura et al. The absence of a lipoprotein envelope in most plant viruses probably represents an adaptation to the evolution of the CW in contrast to the enveloped viruses entering animal cells without CWs.
In the few enveloped plant virus genera, i. Interestingly, the CW of Chlorella spp. After enzymatic digestion of the CW, PBCV-1 gets fused to the cell membrane via the lipid bilayer membrane underneath the outer glycoprotein capsid and translocates its genome in the algae host Van Etten, A successful viral infection relies on the ability of viruses to overcome multiple barriers and move from cell to cell Zhong et al. In animal systems, two main biological strategies are known for an efficient virus cell-to-cell transmission.
Viruses may exploit existing cell-cell interactions, such as neurological or immunological synapses or they may establish cell-cell contacts between cells that are not normally in physical contact Figure 2A. The ability to utilize and manipulate cell-cell contact contributes to the success of viral infections. Virus infections can upregulate endogenous cell adhesion molecules CAM , such as the protein ICAM-1, as well as other components of the extracellular matrix Nakachi et al.
Some viruses can also produce their own adhesion proteins. Extracellular matrix and CW dynamics in the viral cell-to-cell movement. A A schematic representation of a viral synapse between a HIV-1 infected T cell and a receptor-expressing target cell. The adhesion molecules, intercellular adhesion molecule 1 ICAM1 and lymphocyte function-associated antigen 1 LFA1 , engage integrin to stabilize the cellular conjugate.
B Schematic representation of the concerted action of some endogenous and exogenous factors facilitating virus movement throughout PD. After viral penetration, plants reduce size exclusion limit of PDs by locally depositing callose at the neck regions.
Because a plant virus can move through the host via the symplast Kumar et al. Nevertheless, the plant ECM plays a critical role also in traffic regulation in the symplasm. Plasmodesmata PD , the intercellular organelles connecting the symplastic space between individual plant cells Brunkard and Zambryski, are bordered by the PM and surrounded by CW conferring rigidity and shape to the organelle.
Around PDs, the plant ECM is organized in micro-domains with specific composition and metabolism, partially yet unknown Knox and Benitez-Alfonso, Plant viruses move through PD connections either as entire virions or ribonucleoprotein complexes. Different evidence highlight the importance of the ECM in mediating responses to biotic stresses.
ECM is a highly dynamic structure that continuously undergoes controlled remodeling. HCV infection in native liver and its recurrence post-transplant have been shown to significantly affect the deposition and remodeling of extracellular matrix ECM components, particularly collagen, leading to enhanced fibrosis Borg et al. ECM remodeling is often mediated by the activity of specific degradative enzymes. MMPs-mediated remodeling is fundamental for maintenance of the ventricular structure and function during myocarditis, an inflammation of the myocardium associated with necrosis or degeneration of cardiomyocytes caused by many viruses such as enteroviruses, parvovirus B19, adenovirus and HCV.
MMPs, also named matrixins, are calcium-dependent zinc-containing endopeptidases, able to degrade ECM proteins and to process bioactive molecules during pathological conditions, such as inflammation and tissue injury following inflammatory signals. They can mediate changes in ECM and affect immune and pro-inflammatory cell behavior Liu et al. MMP and their inhibitors contribute to the balance between ECM degradation and deposition, coordinating tissue healing Schuurhof et al. Immune responses occur in the context of integrin-mediated adhesive interactions with the ECM.
The plant CW also undergoes specific remodeling events during virus interaction. More generally, demonstration that success of virus infection and callose accumulation around PD are inversely correlated Iglesias and Meins, ; Zavaliev et al. Besides callose accumulation and cellulose content reduction, pectin composition around PD is also different from other CW regions.
The specific composition of the complex group of pectic polysaccharides, prevalently low-methylesterified homogalacturonans HG , found in the pectic microdomain at PDs, can influences CW porosity and rigidity among other factors Orfila and Knox, ; Burton et al. While the mechanisms by which PMEs facilitate viral spread are yet unknown, the relative levels and timing of accumulation of PME and MP at PDs can have different effects on the permeability of the CW barrier and in turn on development of virus infection Bubici et al.
The possibility to revert a tumor immunosuppression by virotherapy represents an interesting strategy to fight tumors. A key limitation is the targeting of the virus to the tumor. The ECM not only precludes virus spread but also virus arrival to the tumor. Therefore, arming the viruses with ECM-degrading enzymes and extending virus permissiveness to non-tumor stromal cells is currently actively explored to improve virus spread and virus constant targeting.
Newcastle disease virus NDV is an avian paramyxovirus with a selective oncolytic effect on tumor cells in culture and in animal models Matveeva et al. ECM limits spread of NDV and other viruses but the removal of tissue collagen and heparan sulfate by means of treatments with collagenase and heparinase before infection increases viral dissemination Yaacov et al.
A deeper understanding of the diverse biological activities and properties of the plant CW must be attained to uncover the many parallel approaches that viruses use to overcome such barrier and eventually design innovative strategies for plant defense. Engineering a plant CW more resistant to virus vector insects, might be one possibility. In fact, aphid salivary secretions contain some CW degrading enzymes, such as polygalacturonases and pectin methylesterases that the insect use for stylet penetration Dreyer and Campbell, A CW more resistant to enzymatic degradation could reduce viral transmission.
The evidence that PMEIs limit viral spread suggests that this class of inhibitor may also be utilized in breeding programs aimed to obtain plant varieties less susceptible to virus diseases. Interestingly, the pectic oligogalacturonides and HA fragments can be perceived as damage-associated molecular patterns DAMP , upon tissue injury or pathogen infection, activating the innate plant and animal immune system, respectively Ferrari et al.
The potential role of these fragments in response to virus infection and relative biotechnological application should be explored. In both plant and animal system, the ECM is of fundamental importance for regulation of active and reciprocal exchange of information between cells. Characteristics and properties of ECMs are also critical for viral entry, transmission and exit, and their differences in plant and animal cells have probably influenced the evolution of structural and functional properties of animal and plant viruses.
The envelope surrounding animal viruses helps avoiding the host immune system and crossing the PM barrier in both directions via endo- and exocytosis, respectively. Plant viruses, coping with a CW that cannot be actively penetrated, cannot make the same use of envelopes but developed expression of unique MPs that facilitate cell-to-cell movement within a host. Despite the differences highlighted above, plant and animal ECMs share many of their compounds, e.
It is striking to observe that in both matrixes viruses can exploit these compounds to enter the host cell, albeit with different strategies. Future efforts are needed to understand the role of specific plant CW polysaccharides around PD in viral cell to cell movement as well as to elucidate possible roles of CW in virus entry.
This knowledge could provide new targets for the genetic improvement of plant resistance to viruses. The role of the ECM in cancer is of particular interest as a significant contributor to tumor progression. Furthermore, the evidence that the matrisome and key ECM remodeling effects can influence certain diseases offers new perspectives for therapeutic intervention.
Current clinical trials using inhibitors of ECM-related targets are ongoing and promising. As the ECM is actively remodeled, targeting specific individual ECM components as well as timing the therapy correctly deserve an intense focus in future research to uncover new targets for future therapy. LS and VL equally participated in drafting, writing and revising the article.
VL prepared the figures. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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