Extracellular Matrix Stiffness Research Articles

Different Decellularization Methods in Bovine Lung Tissue Reveals Distinct Biochemical Composition, Stiffness, and Viscoelasticity in Reconstituted Hydrogels.

Extracellular matrix (ECM)-derived hydrogels are in demand for use in lung tissue engineering to mimic the native microenvironment of cells in vitro. Decellularization of native tissues has been pursued for preserving organotypic ECM while eliminating cellular content and reconstitution into scaffolds which allows re-cellularization for modeling homeostasis, regeneration, or diseases. Achieving mechanical stability and understanding the effects of the decellularization process on mechanical parameters of the reconstituted ECM hydrogels present a challenge in the field. Stiffness and viscoelasticity are important characteristics of tissue mechanics that regulate crucial cellular processes and their in vitro representation in engineered models is a current aspiration. The effect of decellularization on viscoelastic properties of resulting ECM hydrogels has not yet been addressed. The aim of this study was to establish bovine lung tissue decellularization for the first time via pursuing four different protocols and characterization of reconstituted decellularized lung ECM hydrogels for biochemical and mechanical properties. Our data reveal that bovine lungs provide a reproducible alternative to human lungs for disease modeling with optimal retention of ECM components upon decellularization. We demonstrate that the decellularization method significantly affects ECM content, stiffness, and viscoelastic properties of resulting hydrogels. Lastly, we examined the impact of these aspects on viability, morphology, and growth of lung cancer cells, healthy bronchial epithelial cells, and patient-derived lung organoids.

Mechanosensitive (de)regulation of exosome production in tumors.

Cells release membrane-bound nanovesicles (extracellular vesicles) as efficient modes for cell-to-cell communication. Exosomes are nanovesicles produced through the endocytic pathway (involving inwards budding of the endosomal membrane to form multivesicular endosomes, MVEs) and secreted via exocytosis. Tumor-derived exosomes (TEXs) have been implicated in cancer progression and metastasis, with studies showing their role in promoting tumor cell invasion, immune evasion, and pre-metastatic niches. Tumors also leverage dysregulated extracellular matrix (ECM) remodeling mechanisms to create a conducive microenvironment. One such essential mechanical alteration is the stiffening of ECM, which enhances oncogenic signaling pathways leading to tumor progression. Recent experiments have demonstrated ECM stiffness-dependent exosome secretion in various cancer cell lines with higher exosome release on stiff matrix. To capture this mechanobiology-based regulatory axis hijacked by tumors, we suggest a two-pronged mechanosensitive modulation of TEXs. First, using a mesoscale membrane model evolved with Monte Carlo techniques based on the Helfrich Hamiltonian, we show that stiff ECM modulates exosome formation through its effect on cortical tension. Our results suggest an ultrasensitive response of vesicle nucleation induced by curvature-inducing proteins to changes in cortical tension. Second, experimental collaborators have observed Akt-dependent activation of Rabin8 (Guanine Exchange Factor (GEF) of Rab8) along with increased Rab8-mediated exosome secretion on a stiff matrix for transformed cell lines. We capture this mechanosensitive signaling pathway, involved in directing MVE transport to the cellular membrane for exosome release, using an ODE model. Exosome secretion can then be quantified as the combination of formation and trafficking of MVEs. These coarse-grain predictions agree with the experimentally observed change in exosome amount as the matrix stiffens.

Extracellular proteoglycans: A multiscale computational study.

The extracellular matrix (ECM) plays an important role in cell migration and proliferation, and hence in the progression of malignant tumors. Healthy brain is one of the softest tissues, but in cancer, the stiffness of the brain ECM can increase by one or two orders of magnitude. Within the framework of studying mechanotransduction in brain tumors, we aim to construct a multiscale computational model of the brain ECM. In contrast to most tissues whose mechanical properties are governed primarily by collagen, the brain ECM is mainly composed of proteoglycans and hyaluronic acid. During cancer, expression of different proteoglycans is altered during remodeling of the brain ECM.

Cancer-associated fibroblasts in a 3D engineered tissue model induce tumor-like matrix stiffening and EMT transition.

There is an increasing need for the use of 3D in vitro models over 2D culture. Yet, most models remain unable to fully reproduce the complexity observed in vivo. Tissue-engineered models based on the self-assembly method have the potential to better recapitulate the stroma architecture, composition, and cell heterogeneity. Here, we used the self-assembly method and a bladder tissue model to engineer a tumor-like environment, and validated its relevance as a cancer model. The bioengineered bladder cancer model was reconstituted using healthy primary fibroblasts (HFs) and a sub-population of induced cancer-associated fibroblast-like cells (iCAFs) along with a normal urothelium overlay. The iCAFs-derived extracellular matrix (ECM) composition was found to be more fibrotic with increased collagen remodeling and altered fibronectin content. Moreover, the average stiffness of the ECM scaffolds produced by the iCAFs was 7.4 kPa compared to 1.3 kPa for those produced by HFs. In line with those results, urothelial cells overlaid on the iCAFs-derived ECM was found to be more contractile. We also observed increased nuclear translocation of the mechanosensor YAP1 in urothelial cells overlaid on these iCAFs-derived ECM. Furthermore, urothelial cells seeded on iCAFs-derived stroma displayed invasive behavior compared to urothelial cells on HFs. As increased ECM stiffness and cell contractility are associated with the epithelial-to-mesenchymal transition (EMT), we showed an increase expression of the mesenchymal EMT markers, vimentin and ZEB1, within the urothelium on the iCAFs-derived ECM. Overall, our tissue-engineered tumor model achieved stiffness levels comparable to those observed in bladder cancers along with CAF-mediated ECM remodeling, while the urothelium displayed the biological responses that would be expected within a tumor-like environment. Future experiments will take advantage of the 3D and in vivo-like properties of our engineered model to investigate tumor cell invasion.

Pattern formation via cell–cell adhesion and contact inhibition of locomotion in active matter

Cell wetting and dewetting in soft substrates present a collection of non-cohesive and cohesive patterns. Prediction of this wide diversity is of critical importance in order to design experiments with polar active matter under confinement. Although in vivo, cells and the extracellular matrix (ECM) are enfolded by flexible substrates, at experimental realizations, hard boundaries are frequently employed. Here, the elastic forces exerted by the cells and the ECM—between a deformable layer and a solid substrate—allow to recast a continuum model that takes account of heterogeneous exchanges such as cell–substrate adhesion and averaged repolarization due to contact inhibition of locomotion (CIL). Theoretical results show that cell aggregation is enforced as increasing cell–cell adhesion and decreasing CIL strength and exhibit different phases from gaseous states to polar liquids and 3D clusters, in agreement with recent reports. Cell diffusion grows as cell rigidity increases, and reduction of ECM stiffness eases cell aggregation and cluster formation. The findings of this work provide the mechanisms that drive and resist active unstable states and can be used as a predictability tool in cell clustering and cell migration experiments.

PIEZO1-Related Physiological and Pathological Processes in CNS: Focus on the Gliomas.

PIEZO1 is ubiquitously expressed in cells in different kinds of tissues throughout the body, which can sense physical or mechanical stimuli and translate them into intracellular electrochemical signals to regulate organism functions. In particular, PIEZO1 appears in complex interactive regulatory networks as a central node, governing normal and pathological functions in the body. However, the effect and mechanism of the activation or expression of PIEZO1 in diseases of the central nervous system (CNS) remain unclear. On one hand, in CNS diseases, pathophysiological processes in neurons and glial are often accompanied by variations in the mechanical properties of the cellular and extracellular matrix stiffness. The expression of PIEZO1 can therefore be upregulated, in responding to mechanical stimulation, to drive the biological process in cells, which in turns indirectly affects the cellular microenvironment, resulting in alterations of the cellular status. On the other hand, it may have contradictory effects with the change of active patterns and/or subcellular location. This review highlights the biological processes involved with PIEZO1 in CNS cells, with special emphasis on its multiple roles in glioma-associated phenotypes. In conclusion, PIEZO1 can be used as an indicator to assess the malignancy and prognosis of patients with gliomas, as well as a therapeutic target for clinical application following fully exploring the potential mechanism of PIEZO1 in CNS diseases.

The Role of RASSF1C in the Tumor Microenvironment

The tumor microenvironment (TME) plays a vital role in tumor invasion and metastasis and provides a rich environment for identifying novel therapeutic targets. The TME landscape consists of an extracellular matrix (ECM) and stromal cells. ECM is a major component of TME that mediates the interaction between cancer cells and stromal cells to promote invasion and metastasis. We have shown in published work that RASSF1C promotes cancer stem cell development, migration, and drug resistance, in part, by promoting EMT through a mechanism that involves up-regulation of the PIWIL1-piRNA axis. Consistent with this, in this study, we demonstrate that RASSF1C promotes lung cancer metastasis in vivo using an orthotopic mouse model. Interestingly, two target genes identified in a previously conducted microarray study to be up-regulated by RASSF1C in breast and non-small cell lung cancer (NSCLC) cells are prolyl 4-hydroxylase alpha-2 (P4HA2) and procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2). In cancer, P4H2A and PLOD2 are vital for collagen posttranslational modification and folding leading to the formation of a stiff ECM and induction of EMT and cancer stem cell marker gene expression, resulting in metastatic dissemination. Here, we also show that overexpression of RASSF1C up-regulates Collagen I, P4HA2, and PLOD2 in vitro. Up-regulation of P4HA2 and PLOD2 by RASSF1C was also confirmed in lung and breast cancer cells in vivo using mouse models. Further, we found that treatment of wildtype lung cancer cells or lung cancer cells overexpressing RASSF1C or PIWIL1 with piR-35127 and 46545 (both down-regulated by RASSF1C) decreased lung cancer cell invasion/migration. Taken together, our findings suggest that RASSF1C may promote lung cancer cell ECM remodeling to induce lung cancer cell stemness, invasion, and metastasis, in part, by up-regulating a previously unknown PIWIL1-P4HA2-PLOD2 pathway. Furthermore, piR-35127 and piR-46545 could potentially be important anti-metastatic tools.

An in silico study on the influence of extracellular matrix mechanics on vasculogenesis

Background and objectives: Blood vessels form a network of capillaries throughout the body that perform essential functions for life. Vasculogenesis, i.e. the formation of new blood vessels, is regulated by many factors, biochemical ones being among the most important. However, others such as the biomechanical influence on shape, organization and structure of vessel networks require further investigation. In this paper, we develop a 3D agent-based mechanobiological model of vasculogenesis with the aim of analyzing how the mechanics of the extracellular matrix (ECM) affects vasculogenesis. Methods: For this purpose, we consider a growing domain composed of different cells: tip cells, which are the driving cells located at the end of the vessels and stalk cells, which are found in the interior of the vascular network. ECM is considered as particles (agents) that surround the growth of the vascular network. Depending on the cell type, different sets of forces are considered, such as chemotactic, mechanical, random and viscoelastic forces among others. Results: The growth of the network is iteratively analyzed and updated at each time step based on a mechanically-driven proliferation rule. The influence of different biomechanical factors, such as ECM stiffness or viscoelasticity are explored through in silico simulations. A number of indicators are defined along the algorithm, like number of cells, branches, tortuosity and anisotropy, in order to compare topological differences of the vascular network during vasculogenesis under different ECM conditions. The obtained results are qualitatively compared with other related works in the literature. Conclusions: The present study sheds some light and partially explain, from an in silico perspective, the role of ECM mechanics on vasculogenesis. The main conclusions of this work are: (i) increased stiffness increases proliferation, (ii) the network tends to migrate towards stiffer areas, and (iii) increased viscoelasticity decreases proliferation.

Substrate stiffness controls proinflammatory responses in human gingival fibroblasts

Soft gingiva is often compromised in gingival health; however, the underlying biological mechanisms remain unknown. Extracellular matrix (ECM) stiffness is involved in the progression of various fibroblast-related inflammatory disorders via cellular mechanotransduction. Gingival stiffness might regulate cellular mechanotransduction-mediated proinflammatory responses in gingival fibroblasts. This in vitro study aims to investigate the effects of substrate stiffness on proinflammatory responses in human gingival fibroblasts (hGFs). The hGFs isolated from two healthy donors cultured on type I collagen-coated polydimethylsiloxane substrates with different stiffnesses, representing soft (5 kPa) or hard (25 kPa) gingiva. Expression levels of proinflammatory mediators, prostaglandin E2 or interleukin-1β, in hGFs were significantly higher with the soft substrate than with the hard substrate, even without and with lipopolysaccharide (LPS) to induce inflammation. Expression levels of gingival ECM and collagen cross-linking agents in hGFs were downregulated more with the soft substrate than with the hard substrate through 14 days of culture. The soft substrate suppressed the expression of mechanotransduction-related transcriptional factors and activated the expression of inflammation-related factors, whereas the hard substrate demonstrated the opposite effects. Soft substrate induced proinflammatory responses and inhibition of ECM synthesis in hGFs by inactivating cellular mechanotransduction. This supports the importance of ECM stiffness in gingival health.

Extracellular matrix stiffness mediates uterine repair via the Rap1a/ARHGAP35/RhoA/F-actin/YAP axis

The integrity of the structure and function of the endometrium is essential for the maintenance of fertility. However, the repair mechanisms of uterine injury remain largely unknown. Here, we showed that the disturbance of mechanical cue homeostasis occurs after uterine injury. Applying a multimodal approach, we identified YAP as a sensor of biophysical forces that drives endometrial regeneration. Through protein activation level analysis of the combinatorial space of mechanical force strength and of the presence of particular kinase inhibitors and gene silencing reagents, we demonstrated that mechanical cues related to extracellular matrix rigidity can turn off the Rap1a switch, leading to the inactivation of ARHGAP35and then induced activation of RhoA, which in turn depends on the polymerization of the agonist protein F-actin to activate YAP. Further study confirmed that mechanotransduction significantly accelerates remodeling of the uterus by promoting the proliferation of endometrial stromal cells in vitro and in vivo. These studies provide new insights into the dynamic regulatory mechanisms behind uterine remodeling and the function of mechanotransduction.B4ojxzzgfZhteej7Gc57h4Video

The Stiffness-Sensitive Transcriptome of Human Tendon Stromal Cells.

Extracellular matrix stiffness is a major regulator of cellular states. Stiffness-sensing investigations are typically performed using cells that have acquired "mechanical memory" through prolonged conditioning in rigid environments, e.g., tissue culture plastic(TCP). This potentially masks the full extent of the matrix stiffness-driven mechanosensing programs. Here, a biomaterial composed of 2D mechanovariant silicone substrates with simplified and scalable surface biofunctionalization chemistry is developed to facilitate large-scale cell culture expansion processes. Using RNA sequencing, stiffness-mediated mechano-responses of human tendon-derived stromal cells are broadly mapped. Matrix elasticity (E.) approximating tendon microscale stiffness range (E.≈ 35kPa) distinctly favors transcriptional programs related to chromatin remodeling and Hippo signaling; whereas compliant stiffnesses (E. ≈ 2kPa) are enriched in processes related to cell stemness, synapse assembly, and angiogenesis. While tendon stromal cells undergo dramatic phenotypic drift on conventional TCP, mechanovariant substrates abrogate this activation with tenogenic stiffnesses inducing a transcriptional program that strongly correlates with established tendon tissue-specific expression signature. Computational inference predicts that AKT1 and ERK1/2 are major stiffness-sensing signaling hubs. Together, these findings highlight how matrix biophysical cues may dictate the transcriptional identity of tendon cells, and how matrix mechano-reciprocity regulates diverse sets of previously underappreciated mechanosensitive processes in tendon fibroblasts.

Extracellular Matrix Rigidities Regulate the Tricarboxylic Acid Cycle and Antibiotic Resistance of Three-Dimensionally Confined Bacterial Microcolonies.

As a major cause of clinical chronic infection, microbial biofilms/microcolonies in host tissues essentially live in 3D-constrained microenvironments, which potentially modulate their spatial self-organization and morphodynamics. However, it still remains unclear whether and how mechanical cues of 3D confined microenvironments, for example, extracellular matrix (ECM) stiffness, exert an impact on antibiotic resistance of bacterial biofilms/microcolonies. With a high-throughput antibiotic sensitivity testing (AST) platform, it is revealed that 3D ECM rigidities greatly modulate their resistance to diverse antibiotics. The microcolonies in 3D ECM with human tissue-specific rigidities varying from 0.5 to 20kPa show a ≈2-10 000-fold increase in minimum inhibitory concentration, depending on the types of antibiotics. The authors subsequently identified that the increase in 3D ECM rigidities leads to the downregulation of the tricarboxylic acid (TCA) cycle, which is responsible for enhanced antibiotic resistance. Further, it is shown that fumarate, as a potentiator of TCA cycle activity, can alleviate the elevated antibiotic resistance and thus remarkably improve the efficacy of antibiotics against bacterial microcolonies in 3D confined ECM, as confirmed in the chronic infection mice model. These findings suggest fumarate can be employed as an antibiotic adjuvant to effectively treat infections induced by bacterial biofilms/microcolonies in a 3D-confined environment.

Mechanosensitive miR-99b mediates the regulatory effect of matrix stiffness on bone marrow mesenchymal stem cell fate both in vitro and in vivo.

Mechanical signals from extracellular matrix stiffness are important cues that regulate the proliferation and differentiation of bone marrow mesenchymal stem cells (BMSCs). However, the incorporation of BMSCs into soft hydrogels and the dominance of soft matrices for BMSC growth and differentiation limit the directed differentiation of BMSCs incorporated into hydrogels for tissue engineering, especially osteogenesis. Here, we found that the expression of miR-99b increased with increasing hydrogel stiffness and that miR-99b regulated the proliferation and differentiation of BMSCs seeded on the surface of substrates with different stiffnesses. Furthermore, miR-99b significantly promoted the migration of BMSCs in 3D hydrogels. Mechanistically, we demonstrated that matrix stiffness-sensitive miR-99b targets the mammalian target of the rapamycin signaling pathway to regulate the adipogenic and osteogenic differentiation of BMSCs. In addition, by modulating the expression of miR-99b, the osteogenic differentiation of BMSCs in soft 3D hydrogels was promoted. Consistently, the flexible BMSC-GelMA hydrogel transfected with miR-99b significantly promoted bone regeneration in the rat calvarial defect area. These results suggest that miR-99b plays a key role in the mechanotransduction and phenotypic transformation of BMSCs and may inspire new tissue engineering applications with MSCs as key components.

Tumor decellularization reveals proteomic and mechanical characteristics of the extracellular matrix of primary liver cancer

Tumor initiation and progression are critically dependent on interaction of cancer cells with their cellular and extracellular microenvironment. Alterations in the composition, integrity, and mechanical properties of the extracellular matrix (ECM) dictate tumor processes including cell proliferation, migration, and invasion. Also in primary liver cancer, consisting of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), the dysregulation of the extracellular environment by liver fibrosis and tumor desmoplasia is pertinent. Yet, the exact changes occurring in liver cancer ECM remain uncharacterized and underlying tumor-promoting mechanisms remain largely unknown. Herein, an integrative molecular and mechanical approach is used to extensively characterize the ECM of HCC and CCA tumors by utilizing an optimized decellularization technique. We identified a myriad of proteins in both tumor and adjacent liver tissue, uncovering distinct malignancy-related ECM signatures. The resolution of this approach unveiled additional ECM-related proteins compared to large liver cancer transcriptomic datasets. The differences in ECM protein composition resulted in divergent mechanical properties on a macro- and micro-scale that are tumor-type specific. Furthermore, the decellularized tumor ECM was employed to create a tumor-specific hydrogel that supports patient-derived tumor organoids, which provides a new avenue for personalized medicine applications. Taken together, this study contributes to a better understanding of alterations to composition, stiffness, and collagen alignment of the tumor ECM that occur during liver cancer development.

Cardiovascular Mechano-Epigenetics: Force-Dependent Regulation of Histone Modifications and Gene Regulation.

The local mechanical microenvironment impacts on the cell behavior. In the cardiovascular system, cells in both the heart and the vessels are exposed to continuous blood flow, blood pressure, stretching forces, and changing extracellular matrix stiffness. The force-induced signals travel all the way to the nucleus regulating epigenetic changes such as chromatin dynamics and gene expression. Mechanical cues are needed at the very early stage for a faultless embryological development, while later in life, aberrant mechanical signaling can lead to a range of pathologies, including diverse cardiovascular diseases. Hence, an investigation of force-generated epigenetic alteration at different time scales is needed to understand fully the phenotypic changes in disease onset and progression. That being so, cardiovascular mechano-epigenetics emerges as an attractive field of study. Given the rapid advances in this emergent field of research, this short review aims to provide an analysis of the state of knowledge of force-induced epigenetic changes in the cardiovascular field.

Regulators, functions, and mechanotransduction pathways of matrix stiffness in hepatic disease.

The extracellular matrix (ECM) provides physical support and imparts significant biochemical and mechanical cues to cells. Matrix stiffening is a hallmark of liver fibrosis and is associated with many hepatic diseases, especially liver cirrhosis and carcinoma. Increased matrix stiffness is not only a consequence of liver fibrosis but is also recognized as an active driver in the progression of fibrotic hepatic disease. In this article, we provide a comprehensive view of the role of matrix stiffness in the pathological progression of hepatic disease. The regulators that modulate matrix stiffness including ECM components, MMPs, and crosslinking modifications are discussed. The latest advances of the research on the matrix mechanics in regulating intercellular signaling and cell phenotype are classified, especially for hepatic stellate cells, hepatocytes, and immunocytes. The molecular mechanism that sensing and transducing mechanical signaling is highlighted. The current progress of ECM stiffness's role in hepatic cirrhosis and liver cancer is introduced and summarized. Finally, the recent trials targeting ECM stiffness for the treatment of liver disease are detailed.

Dynamic Magneto-Softening of 3D Hydrogel Reverses Malignant Transformation of Cancer Cells and Enhances Drug Efficacy.

High extracellular matrix stiffness is a prominent feature of malignant tumors associated with poor clinical prognosis. To elucidate mechanistic connections between increased matrix stiffness and tumor progression, a variety of hydrogel scaffolds with dynamic changes in stiffness have been developed. These approaches, however, are not biocompatible at high temperature, strong irradiation, and acidic/basic pH, often lack reversibility (can only stiffen and not soften), and do not allow study on the same cell population longitudinally. In this work, we develop a dynamic 3D magnetic hydrogel whose matrix stiffness can be wirelessly and reversibly stiffened and softened multiple times with different rates of change using an external magnet. With this platform, we found that matrix stiffness increased tumor malignancy including denser cell organization, epithelial-to-mesenchymal transition and hypoxia. More interestingly, these malignant transformations could be halted or reversed with matrix softening (i.e., mechanical rescue), to potentiate drug efficacy attributing to reduced solid stress from matrix and downregulation of cell mechano-transductors including YAP1. We propose that our platform can be used to deepen understanding of the impact of matrix softening on cancer biology, an important but rarely studied phenomenon.

Age-related matrix stiffening epigenetically regulates α-Klotho expression and compromises chondrocyte integrity

Extracellular matrix stiffening is a quintessential feature of cartilage aging, a leading cause of knee osteoarthritis. Yet, the downstream molecular and cellular consequences of age-related biophysical alterations are poorly understood. Here, we show that epigenetic regulation of α-Klotho represents a novel mechanosensitive mechanism by which the aged extracellular matrix influences chondrocyte physiology. Using mass spectrometry proteomics followed by a series of genetic and pharmacological manipulations, we discovered that increased matrix stiffness drove Klotho promoter methylation, downregulated Klotho gene expression, and accelerated chondrocyte senescence in vitro. In contrast, exposing aged chondrocytes to a soft matrix restored a more youthful phenotype in vitro and enhanced cartilage integrity in vivo. Our findings demonstrate that age-related alterations in extracellular matrix biophysical properties initiate pathogenic mechanotransductive signaling that promotes Klotho promoter methylation and compromises cellular health. These findings are likely to have broad implications even beyond cartilage for the field of aging research.

Severe COVID-19-A Review of Suggested Mechanisms Based on the Role of Extracellular Matrix Stiffness.

The severity of COVID-19 commonly depends on age-related tissue stiffness. The aim was to review publications that explain the effect of microenvironmental extracellular matrix stiffness on cellular processes. Platelets and endothelial cells are mechanosensitive. Increased tissue stiffness can trigger cytokine storm with the upregulated expression of pro-inflammatory cytokines, such as tumor necrosis factor alpha and interleukin IL-6, and tissue integrity disruption, leading to enhanced virus entry and disease severity. Increased tissue stiffness in critically ill COVID-19 patients triggers platelet activation and initiates plague formation and thrombosis development. Cholesterol content in cell membrane increases with aging and further enhances tissue stiffness. Membrane cholesterol depletion decreases virus entry to host cells. Membrane cholesterol lowering drugs, such as statins or novel chitosan derivatives, have to be further developed for application in COVID-19 treatment. Statins are also known to decrease arterial stiffness mitigating cardiovascular diseases. Sulfated chitosan derivatives can be further developed for potential use in future as anticoagulants in prevention of severe COVID-19. Anti-TNF-α therapies as well as destiffening therapies have been suggested to combat severe COVID-19. The inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells pathway must be considered as a therapeutic target in the treatment of severe COVID-19 patients. The activation of mechanosensitive platelets by higher matrix stiffness increases their adhesion and the risk of thrombus formation, thus enhancing the severity of COVID-19.

Meet the First Authors.

Meet the First Authors.