Bibliometric analysis of the global research status and trends of mechanotransduction in cancer

BACKGROUND The development of cancer is thought to involve the dynamic crosstalk between the tumor cells and the microenvironment they inhabit.Such crosstalk is thought to involve mechanotransduction,a process whereby the cells sense mechanical cues such as stiffness,and translate these into biochemical signals,which have an impact on the subsequent cellular activities.Bibliometric analysis is a statistical method that involves investigating different aspects(including authors’names and affiliations,article keywords,journals and citations)of large volumes of literature.Despite an increase in mechanotransduction-related research in recent years,there are currently no bibliometric studies that describe the global status and trends of mechanotransduction-related research in the cancer field.AIM To investigate the global research status and trends of mechanotransduction in cancer from a bibliometric viewpoint.METHODS Literature on mechanotransduction in cancer published from January 1,1900 to December 31,2022 was retrieved from the Web of Science Core Collection.Excel and GraphPad software carried out the statistical analysis of the relevant author,journal,organization,and country information.The co-authorship,keyword cooccurrence,and keyword burst analysis were visualized with VOSviewer and CiteSpace.RESULTS Of 597 publications from 745 institutions in 45 countries were published in 268 journals with 35510 citation times.With 270 articles,the United States is a well-established global leader in this field,and the University of California system,the most productive(n=36)and influential institution(n=4705 citations),is the most highly active in collaborating with other organizations.Cancers was the most frequent publisher with the highest H-index.The most productive researcher was Valerie M.Weaver,with 10 publications.The combined analysis of concurrent and burst keywords revealed that the future research hotspots of mechanotransduction in cancer were related to the plasma membrane,autophagy,piezo1/2,heterogeneity,cancer diagnosis,and post-transcriptional modifications.CONCLUSION Mechanotransduction-related cancer research remains a hot topic.The United States is in the leading position of global research on mechano-oncology after almost 30 years of investigations.Research group cooperations exist but remain largely domestic,lacking cross-national communications.The next big topic in this field is to explore how the plasma membrane and its localized mechanosensor can transduce mechanical force through post-transcriptional modifications and thereby participate in cellular activity regulations and cancer development.

Mechanotransduction of stem cells for tendon repair

Tendon is a mechanosensitive tissue that transmits force from muscle to bone.Physiological loading contributes to maintaining the homeostasis and adaptation of tendon,but aberrant loading may lead to injury or failed repair.It is shown that stem cells respond to mechanical loading and play an essential role in both acute and chronic injuries,as well as in tendon repair.In the process of mechanotransduction,mechanical loading is detected by mechanosensors that regulate cell differentiation and proliferation via several signaling pathways.In order to better understand the stem-cell response to mechanical stimulation and the potential mechanism of the tendon repair process,in this review,we summarize the source and role of endogenous and exogenous stem cells active in tendon repair,describe the mechanical response of stem cells,and finally,highlight the mechanotransduction process and underlying signaling pathways.

Mechanotransduction,nanotechnology,and nanomedicine

Mechanotransduction,a conversion of mechanical forces into biochemical signals,is essential for human development and physiology.It is observable at all levels ranging from the whole body,organs,tissues,organelles down to molecules.Dysregulation results in various diseases such as muscular dystrophies,hypertension-induced vascular and cardiac hypertrophy,altered bone repair and cell deaths.Since mechanotransduction occurs at nanoscale,nanosciences and applied nanotechnology are powerful for studying molecular mechanisms and pathways of mechanotransduction.Atomic force microscopy,magnetic and optical tweezers are commonly used for force measurement and manipulation at the single molecular level.Force is also used to control cells,topographically and mechanically by specific types of nano materials for tissue engineering.Mechanotransduction research will become increasingly important as a sub-discipline under nanomedicine.Here we review nanotechnology approaches using force measurements and manipulations at the molecular and cellular levels during mechanotransduction,which has been increasingly play important role in the advancement of nanomedicine.

Mechanotransduction-The relationship between gravity,cells and tensile loading in extracellular matrix

Gravity plays a central role in vertebrate development and evolution.Mechanotransduction involves the tensile tethering of veins and arteries,connections between the epidermis and dermis in skin,tensile stress concentrations that occur at tissue interfaces,cell-cell interactions,cell-collagen fiber stress transfer in extracellular matrix and fluid shear flow.While attention in the past has been directed at understanding the myriad of biochemical players associated with mechanotransduction pathways,less attention has been focused on determining the tensile mechanical behavior of tissues in vivo.Fibroblasts sit on the surface of collagen fibers in living skin and exert a retractile force on the fibers.This retractile force pulls against the tension in collagen fibers in skin.After fibroblast-collagen fiber interactions are altered either by changes in fibroblast adhesion or after formation of cancer associated fibroblasts,and changes in cell junctions,alterations in the retractive force leads to changes in mechanotransduction.The purpose of this paper is to present a model of tensile forces that occur at the fibroblast-collagen fiber interface and how these forces are important in extracellular matrix physiology in health and disease.

Nuclear Mechanotransduction in Cellular Mechanobiology and Molecular Mechanomedicine

It is known that mechanical forces play critical roles in physiology and diseases but the underlying mechanisms remain largely unknown[1].Most studies on the role of forces focus on cell surface molecules and cytoplasmic proteins.However,increasing evidence suggests that nuclear mechanotransduction impacts nuclear activities and functions.Recently we have revealed that transgene dihydrofolate reductase(DHFR)gene expression is directly upregulated via cell surface forceinduced stretching of chromatin [2].Here we show that endogenous genes are also upregulated directly by force via integrins.We present evidence on an underlying mechanism of how gene transcription is regulated by force.We have developed a technique of elastic round microgels to quantify 3D tractions in vitro and in vivo[3].We report a synthetic small molecule(which has been stiffened structurally)that inhibits malignant tumor repopulating cell growth in a low-stiffness(force)microenvironment and cancer metastasis in mouse models without detectable toxicity[4].These findings suggest that direct nuclear mechanotransduction impacts mechanobiology and mechanomedicine at cellular and molecular levels.

Nuclear Mechanotransduction under Geometric Constraint

Cells in vivo reside within a complex microenvironment that is rich in biological,chemical and mechanical cues,playing critical roles in regulating cellular activities(e.g.,proliferation,migration,differentiation)both spatially and temporally.Although it is well accepted that biochemical cues can significantly influence cell functions,accumulating evidence has also shown that mechanical feedback from the cell microenvironment(e.g.,stiffness of ECM,morphology,and tension force)also plays an important role in controlling cell fate.Disequilibrium of the mechanical microenvironment is associated with a series of diseases,such as cancer migration and tissue fibrosis.Thus,there is a pressing need to understand how cells transduce these mechanobiological cues.The cell cytoskeleton is linked to both the nuclear lamina via LINC complexes and to focal adhesions.This enables the intriguing possibility that forces directly transduced by the nucleus might in fact affect gene expression.Can force transmitted to nucleus and associated alterations to the special organization of genome inside the nucleus modulate gene expression programmes and change cell behaviors? This kind of putative mechanotransduction dominated by the nucleus is termed as nuclear mechanotransduction.Evidence shows that isolated nuclei regulate their stiffness to in response to force applied on nesprin with integrated nuclear lamina and emerin required.Another example is that the force applied on integrins in focal adhesions can be transmitted through actin filaments to the LINC complex and then stretch the chromatin directly through lamina-chromatin interactions.However,the mechanism of nuclear mechanotransduction is still unclear.Three hypotheses have been proposed.The first proposed mechanism is that the proteins on the nuclear lamina are phosphorylated induced by force and their special organization is changed to regulate downstream signal transduction.Transcription factors like YAP and calcium ions would enter the nucleus in the context of force stretching the nuclear lamina and opening nuclear pore complexes(NPC)and calcium channels.Another proposed hypothesis in this case is that force propagated through the cytoskeleton stretches,opens or condenses chromatin directly,leading to an entirely different genome organization.Nevertheless,due to the lack of research methods and instruments,researchers have not reached a consensus on how cells sense external forces and react specifically through nucleus.In this study,we used micropatterned techniques to modify poly(N-isopropyl-acrylamide)(PA)hydrogel surface with fibronectin(FN)which promote cell adhesion to shape-engineer the cells to investigate the effects of matrix stiffness on nuclear mechanotransduction.To illustrate the impact on nuclear shape induced by matrix stiffness,the nuclei were stained byDAPI and observed by a laser confocal microscopy with small step sizes.The nuclear shape index(NSI),which indicate the variation of projected nuclear shape was firstly researched thoroughly.Meanwhile,the nuclear height,width and volume were characterized in this study.To investigate the force transmitted to the nuclei in cells cultured on hydrogels with multiple stiffness,the cell traction force was measured and the cytoskeleton like actin cap was studied by pharmacological treatments.We also found that the impacts of matrix stiffness on nuclear mechanics,which indicated by the condensation of chromatin and the overexpression of Lamin A/C.

Ultrasound mechanotransduction on osteoblastic mineralization and mitigating bone loss

Introduction Mechanotransduction has demonstrated potentials for tissue adaptation in vivo and in vitro. It is well documented that ultrasound,as a mechanical signal,can produce a wide variety of biological effects in vitro and in vivo [1]. As an example,

Tuning mesenchymal stem cell secretome therapeutic potential through mechanotransduction

Mesenchymal stem cells(MSCs)and their byproducts have been widely validated as potential therapeutic products for regenerative medicine.The therapeutic effects result mainly from the paracrine activity of MSCs,which consists of the secretion of bioactive molecules,whether dispersed in medium conditioned by cell culture or encapsulated in extracellular vesicles.The composition of the MSC secretome,which represents the set of these secreted cellular products,is crucial for the performance of the desired therapeutic functions.Different cell culture strategies have been employed to adjust the secretome composition of MSCs to obtain the best therapeutic responses for different clinical contexts.However,the manipulation of culture conditions has focused mainly on the use of different biochemical elements for the preconditioning of MSCs and less on the physical conditions of the cell culture environment.Herein,we offer our point of view regarding the importance of the physical properties of cell culture substrates and their mechanotransduction responses in preconditioning the MSCs secretome.We highlight the relevance of studying mechanotransduction events associating cell morphology and the modulation of gene expression to customize and expand the use of MSCs secretomes.

Polycystins and mechanotransduction: From physiology to disease

Polycystins are key mechanosensor proteins able to respond to mechanical forces of external or internal origin. They are widely expressed in primary cilium and plasma membrane of several cell types including kidney, vascular endothelial and smooth muscle cells,osteoblasts and cardiac myocytes modulating their physiology. Interaction of polycystins with diverse ion channels, cell-cell and cell-extracellular matrix junctional proteins implicates them in the regulation of cell structure, mechanical force transmission and mechanotransduction. Their intracellular localization in endoplasmic reticulum further regulates subcellular trafficking and calcium homeostasis, finely-tuning overall cellular mechanosensitivity. Aberrant expression or genetic alterations of polycystins lead to severe structural and mechanosensing abnormalities including cyst formation, deregulated flow sensing, aneurysms,defective bone development and cancer progression,highlighting their vital role in human physiology.

Mechanotransduction in bone: Intervening in health and disease

Mechanotransduction has been proven to be one of the most significant variables in bone remodeling and its alterations have been shown to result in a variety of bone diseases. Osteoporosis, Paget's disease, orthopedic disorders, osteopetrosis as well as hyperparathyroidism and hyperthyroidism all comprise conditions which have been linked with deregulated bone remodeling. Although the significance of mechanotransduction for bone health and disease is unquestionable, the mechanisms behind this important process have not been fully understood. This review will discuss the molecules that have been found to be implicated in mechanotransduction, as well as the mechanisms underlying bone health and disease, emphasizing on what is already known as well as new molecules potentially taking part in conveying mechanical signals from the cell surface towards the nucleus under physiological or pathologic conditions. It will also focus on the model systems currently used in mechanotransduction studies, like osteoblast-like cells as well as three-dimensional constructs and their applications among others. It will also examine the role of mechanostimulatory techniques in preventing and treating bone degenerative diseases and consider theirapplications in osteoporosis, craniofacial development, skeletal deregulations, fracture treatment, neurologic injuries following stroke or spinal cord injury, dentistry, hearing problems and bone implant integration in the near future.

Mechanism and application of feedback loops formed by mechanotransduction and histone modifications

Mechanical stimulation is the key physical factor in cell environment.Mechanotransduction acts as a fundamental regulator of cell behavior,regulating cell proliferation,differentiation,apoptosis,and exhibiting specific signature alterations during the pathological process.As research continues,the role of epigenetic science in mechanotransduction is attracting attention.However,the molecular mechanism of the synergistic effect between mechanotransduction and epigenetics in physiological and pathological processes has not been clarified.We focus on how histone modifications,as important components of epigenetics,are coordinated with multiple signaling pathways to control cell fate and disease progression.Specifically,we propose that histone modifications can form regulatory feedback loops with signaling pathways,that is,histone modifications can not only serve as downstream regulators of signaling pathways for target gene transcription but also provide feedback to regulate signaling pathways.Mechanotransduction and epigenetic changes could be potential markers and therapeutic targets in clinical practice.

Emerging role of lncRNAs as mechanical signaling molecules in mechanotransduction and their association with Hippo-YAP signaling:a review

Cells within tissues are subject to various mechanical forces,including hydrostatic pressure,shear stress,compression,and tension.These mechanical stimuli can be converted into biochemical signals through mechanoreceptors or cytoskeleton-dependent response processes,shaping the microenvironment and maintaining cellular physiological balance.Several studies have demonstrated the roles of Yes-associated protein(YAP)and its homolog transcriptional coactivator with PDZ-binding motif(TAZ)as mechanotransducers,exerting dynamic influence on cellular phenotypes including differentiation and disease pathogenesis.This regulatory function entails the involvement of the cytoskeleton,nucleoskeleton,integrin,focal adhesions(FAs),and the integration of multiple signaling pathways,including extracellular signal-regulated kinase(ERK),wingless/integrated(WNT),and Hippo signaling.Furthermore,emerging evidence substantiates the implication of long non-coding RNAs(lncRNAs)as mechanosensitive molecules in cellular mechanotransduction.In this review,we discuss the mechanisms through which YAP/TAZ and lncRNAs serve as effectors in responding to mechanical stimuli.Additionally,we summarize and elaborate on the crucial signal molecules involved in mechanotransduction.

Matrix stiffness regulates osteoclast fate through integrin-dependent mechanotransduction

Osteoclasts ubiquitously participate in bone homeostasis,and their aberration leads to bone diseases,such as osteoporosis.Current clinical strategies by biochemical signaling molecules often perturb innate bone metabolism owing to the uncontrolled management of osteoclasts.Thus,an alternative strategy of precise regulation for osteoclast differentiation is urgently needed.To this end,this study proposed an assumption that mechanic stimulation might be a potential strategy.Here,a hydrogel was created to imitate the physiological bone microenvironment,with stiffnesses ranging from 2.43kPa to 68.2kPa.The impact of matrix stiffness on osteoclast behaviors was thoroughly investigated.Results showed that matrix stiffness could be harnessed for directing osteoclast fate in vitro and in vivo.In particular,increased matrix stiffness inhibited the integrinβ3-responsive RhoA-ROCK2-YAP-related mechanotransduction and promoted osteoclastogenesis.Notably,preosteoclast development is facilitated by medium-stiffness hydrogel(M-gel)possessing the same stiffness as vessel ranging from 17.5 kPa to 44.6 kPa by partial suppression of mechanotransduction,which subsequently encouraged revascularization and bone regeneration in mice with bone defects.Our works provide an innovative approach for finely regulating osteoclast differentiation by selecting the optimum matrix stiffness and enable us further to develop a matrix stiffness-based strategy for bone tissue engineering.

Tunable nano-engineered anisotropic surface for enhanced mechanotransduction and soft-tissue integration

Electrochemically engineered titania(TiO_(2))nanopores enable tailored cellular function;however,the cellular mechanosensing mechanisms dictating the cell response and soft tissue integration are yet to be elucidated.Here,we report the fabrication of anisotropic TiO_(2)nanopores with diameters of 46 and 66 nm on microrough titanium(Ti)via electrochemical anodization,towards short-and long-term guidance of human primary gingival fibroblasts(hGFs).Cells on tissue culture plates and bare Ti substrates were used as controls.Notably,we show that nanopores with a diameter of 66 nm induced more mature focal adhesions of vinculin and paxillin at the membrane,encouraged the development of actin fibers at focal adhesion sites,led to elongated cell and nuclear shape.These topographical-driven changes were attributed to the Ras-related C3 botulinum toxin substrate 1(Rac 1)GTPase pathway and nuclear localisation of LAMIN A/C and yes-associated protein(YAP)and associated with increased ligament differentiation with elevated expression of the ligament marker Mohawk homeobox(MKX).Study findings reveal that minor tuning of nanopore diameter is a powerful tool to explore intracellular and nuclear mechanotransduction and gain insight into the relationships between nanomaterials and mechanoresponsive cellular elements.

Stretchable Electrochemical Sensors: From Electrode Fabrication to Cell Mechanotransduction Monitoring

Electrochemical sensing faces huge challenges in characterizing the transient release of biochemical molecules from deformed cells,due to the severely mechanical mismatch between rigid electrodes and soft cells.In recent years,the emergence of stretchable electrochemical sensors has made a breakthrough by complying with the deformation of living cells and simultaneous monitoring of mechanically evoked biochemical signals.This review first summarizes two fundamental strategies for the fabrication of stretchable electrodes from the points of structure and material.Next,recent progresses in construction of functionalized interface to improve the performance of stretchable electrochemical sensors are presented.Then,the application of stretchable electrochemical sensors in real-time monitoring of biomolecules released by mechanically sensitive cells is introduced.Finally,some perspectives and challenges of stretchable electrochemical sensors regarding cell detection are discussed.

Epigenetic regulation of chondrocytes affected by mitochondria through mechanotransduction in osteoarthritis

Abnormal mechanical loading of articular cartilage is still considered an important pathogenic factor for osteoarthritis(OA).The occurrence and development of OA are accompanied by epigenetic alterations in chondrocytes.As the center of cellular energy metabolism,mitochondria have attracted increasing attention for their epigenetic regulation.Furthermore,mitochondria are mechanosensitive organelles,and abnormal mechanical loading affects chondrocyte epigenetics through the mitochondria,which may be one of the important mechanisms of OA pathogenesis.Well-known mitochondrial metabolites such as acetyl-CoA andα-ketoglutaric acid(α-KG)can be used as cofactors of histone modifying enzymes.Some histone modifying enzymes of lysine specific demethylase(KDMs)family are affected by mitochondrial function.In addition,TCA enzymes in mitochondria can undergo nuclear translocation and help regulate histone modification by catalyzing the generation of corresponding downstream products in the nucleus.However,the specific mechanism of mitochondrial epigenetic regulation of OA progression through chondrocytes remains unclear.Here,we discuss the changes in OA chondrocytes,their physiological activities under the conditions of physiological and supraphysiological mechanical loading,and the potential epigenetic regulation of mechanical loading through chondrocyte mitochondria.The combination of mechanobiological and epigenetic regulation mechanisms will provide new ideas and insights for the prevention and treatment of OA.

Portal hypertension in patients with nonalcoholic fatty liver disease:Current knowledge and challenges

Portal hypertension(PH)has traditionally been observed as a consequence of significant fibrosis and cirrhosis in advanced non-alcoholic fatty liver disease(NAFLD).However,recent studies have provided evidence that PH may develop in earlier stages of NAFLD,suggesting that there are additional pathogenetic mechanisms at work in addition to liver fibrosis.The early development of PH in NAFLD is associated with hepatocellular lipid accumulation and ballooning,leading to the compression of liver sinusoids.External compression and intraluminal obstacles cause mechanical forces such as strain,shear stress and elevated hydrostatic pressure that in turn activate mechanotransduction pathways,resulting in endothelial dysfunction and the development of fibrosis.The spatial distribution of histological and functional changes in the periportal and perisinusoidal areas of the liver lobule are considered responsible for the pre-sinusoidal component of PH in patients with NAFLD.Thus,current diagnostic methods such as hepatic venous pressure gradient(HVPG)measurement tend to underestimate portal pressure(PP)in NAFLD patients,who might decompensate below the HVPG threshold of 10 mmHg,which is traditionally considered the most relevant indicator of clinically significant portal hypertension(CSPH).This creates further challenges in finding a reliable diagnostic method to stratify the prognostic risk in this population of patients.In theory,the measurement of the portal pressure gradient guided by endoscopic ultrasound might overcome the limitations of HVPG measurement by avoiding the influence of the pre-sinusoidal component,but more investigations are needed to test its clinical utility for this indication.Liver and spleen stiffness measurement in combination with platelet count is currently the best-validated non-invasive approach for diagnosing CSPH and varices needing treatment.Lifestyle change remains the cornerstone of the treatment of PH in NAFLD,together with correcting the components of metabolic syndrome,using nonselective beta blockers,whereas emerging candidate drugs require more robust confirmation from clinical trials.

Matrix stiffness exacerbates the proinflammatory responses of vascular smooth muscle cell through the DDR1-DNMT1 mechanotransduction axis

Vascular smooth muscle cell (vSMC) is highly plastic as its phenotype can change in response to mechanical cues inherent to the extracellular matrix (ECM). VSMC may be activated from its quiescent contractile phenotype to a proinflammatory phenotype, whereby the cell secretes chemotactic and inflammatory cytokines, e.g. MCP1 and IL6, to functionally regulate monocyte and macrophage infiltration during the development of various vascular diseases including arteriosclerosis. Here, by culturing vSMCs on polyacrylamide (PA) substrates with variable elastic moduli, we discovered a role of discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase that binds collagens, in mediating the mechanical regulation of vSMC gene expression, phenotype, and proinflammatory responses. We found that ECM stiffness induced DDR1 phosphorylation, oligomerization, and endocytosis to repress the expression of DNA methyltransferase 1 (DNMT1), very likely in a collagen-independent manner. The DDR1-to-DNMT1 signaling was sequentially mediated by the extracellular signal-regulated kinases (ERKs) and p53 pathways. ECM stiffness primed vSMC to a proinflammatory phenotype and this regulation was diminished by DDR1 inhibition. In agreement with the in vitro findings, increased DDR1 phosphorylation was observed in human arterial stiffening. DDR1 inhibition in mouse attenuated the acute injury or adenine diet-induced vascular stiffening and inflammation. Furthermore, mouse vasculature with SMC-specific deletion of Dnmt1 exhibited proinflammatory and stiffening phenotypes. Our study demonstrates a role of SMC DDR1 in perceiving the mechanical microenvironments and down-regulating expression of DNMT1 to result in vascular pathologies and has potential implications for optimization of engineering artificial vascular grafts and vascular networks.

Multi-scale mechanotransduction of the poroelastic signals from osteon to osteocyte in bone tissue

In order to quantify the poroelastic mechanical signals conduction and evaluate the biomechanical effectiveness of functional units(osteocyte processes,canaliculi and lacuna)in lacunar-canalicular system(LCS),a multiscale poroelastic finite element model was established by using the Comsol Multiphysics software.The poroelastic mechanical signals(pore pressure,fluid velocity,von-Mises stress,strain)were analyzed inside the osteon-osteocyte system.The effects of osteocyte(OCY)’s shape(ellipse and circle),long axis directions(horizontal and vertical)and mechanical properties(Elastic modulus and permeability)on its poroelastic responses were examined.It is found that the OCY processes is the best mechanosensor compared with the OCY body,lacunae and canaliculi.The mechanotransduction ability of the elliptic shaped OCY is stronger than that of circular shaped.The pore pressure and flow velocity around OCYs increase as the elastic modulus and permeability of OCY increase.The established model can be used for studying the mechanism of bone mechanotransduction at the multiscale level.

Soft overcomes the hard:Flexible materials adapt to cell adhesion to promote cell mechanotransduction

Cell behaviors and functions show distinct contrast in different mechanical microenvironment.Numerous materials with varied rigidity have been developed to mimic the interactions between cells and their surroundings.However,the conventional static materials cannot fully capture the dynamic alterations at the bio-interface,especially for the molecular motion and the local mechanical changes in nanoscale.As an alternative,flexible materials have great potential to sense and adapt to mechanical changes in such complex microenvironment.The flexible materials could promote the cellular mechanosensing by dynamically adjusting their local mechanics,topography and ligand presentation to adapt to intracellular force generation.This process enables the cells to exhibit comparable or even higher level of mechanotransduction and the downstream‘hard’phenotypes compared to the conventional stiff or rigid ones.Here,we highlight the relevant studies regarding the development of such adaptive materials to mediate cell behaviors across the rigidity limitation on soft substrates.The concept of‘soft overcomes the hard’will guide the future development and application of biological materials.