TGF-β signaling in health and disease

Cell, Journal Year: 2023, Volume and Issue: 186(19), P. 4007 - 4037

Published: Sept. 1, 2023

The TGF-β regulatory system plays crucial roles in the preservation of organismal integrity. signaling controls metazoan embryo development, tissue homeostasis, and injury repair through coordinated effects on cell proliferation, phenotypic plasticity, migration, metabolic adaptation, immune surveillance multiple types shared ecosystems. Defects signaling, particularly epithelial cells, fibroblasts, disrupt tolerance, promote inflammation, underlie pathogenesis fibrosis cancer, contribute to resistance these diseases treatment. Here, we review how coordinates multicellular response programs health disease this knowledge can be leveraged develop treatments for system.

Language: Английский

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Cell–extracellular matrix mechanotransduction in 3D

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 24(7), P. 495 - 516

Published: Feb. 27, 2023

Language: Английский

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Organization, dynamics and mechanoregulation of integrin-mediated cell–ECM adhesions

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 24(2), P. 142 - 161

Published: Sept. 27, 2022

Language: Английский

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Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis

Nature, Journal Year: 2022, Volume and Issue: 610(7931), P. 356 - 365

Published: Oct. 5, 2022

Language: Английский

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Cell–3D matrix interactions: recent advances and opportunities

Trends in Cell Biology, Journal Year: 2022, Volume and Issue: 32(10), P. 883 - 895

Published: April 8, 2022

The diversity of hundreds extracellular matrix (ECM) molecules in different tissues and their interactions are now being documented 'matrisome' databases.Physical properties the 3D ECM, including viscoelasticity microarchitecture, can govern cell adhesion, mechanotransduction, multiple modes migration.New advances ECM biology identifying mechanisms cancer progression fibrosis, as well potential therapeutic targets.Characterizations cell–ECM feedback loops computational modeling providing new insights opportunities for intervention diseases disorders. Tissues consist cells surrounding (ECM). Cell–ECM play crucial roles embryonic development, differentiation, tissue remodeling, fibrosis cancer. Recent research characterizing cell–matrix include detailed descriptions associated molecules, complex intermolecular development disease, identification distinctive migration ECMs, into organ formation. Exploring physical features microenvironments bidirectional regulation signaling organization emphasize dynamic nature these interactions, which that exacerbate disease. Understanding potentially lead to targeted interventions. New on interactionsThe with (see Glossary) during formation adult homeostasis, pathogenesis such This field has expanded explosively after discovery many surface receptors. Our goal this brief review is highlight recent conceptual experimental should provide exciting future cell–3D interactions.Diversity interactionsA starting ~2019 been widespread adoption term – is, comprising it changes disease pathogenesis. holistic concept matrisomes moves beyond classical studies focusing a single protein or family not only structural proteins, collagens, elastin, proteoglycans, fibronectin, but also matrix-associated enzymes inhibitors, matrix-bound growth factors, some cases receptors [1.Karamanos N.K. et al.A guide composition functions matrix.FEBS J. 2021; 288: 6850-6912Crossref PubMed Scopus (65) Google Scholar,2.Izzi V. al.Pan-cancer analysis genomic alterations mutations matrisome.Cancers (Basel). 2020; 12: 2046Crossref (27) Scholar]. Among examples, have used matrisome analyses characterize basement membranes (https://bmbase.manchester.ac.uk/), discover ECM-associated genes more than other [2.Izzi Scholar], identify thrombospondin tenascin links collagen alignment breast [3.Tomko L.A. al.Targeted identifies thrombospondin-2 tenascin-C aligned stroma from invasive carcinoma.Sci. Rep. 2018; 8: 12941Crossref (37) bioengineered models human pancreatic [4.Osuna de la Pena D. al.Bioengineered recapitulate vivo tumour biology.Nat. Commun. 5623Crossref (11) Scholar].Many publications still at descriptive level. There considerable overlaps between components 'adhesome,' comprises adhesions, especially focal adhesions (e.g., see www.adhesome.org). Both 'omics' approaches major applying increasingly sophisticated methods understand involving networks rather just few selected proteins past. Unexpected findings may arise terms groups regulating components. Exemplifying crosstalk, planar membrane two its biochemically unrelated constituents, laminin IV, strongly regulate assembly fibrillar component, variety types [5.Lu al.Basement regulates fibronectin using sliding driven by contractile winch.Dev. Cell. 52: 631-646 e634Abstract Full Text PDF (24) Scholar].We know vary widely depending type biochemical mechanical (Figure 1). Multiple characterized recently range lamellipodial characteristic mesenchymal fibroblast-like rounded amoeboid immune certain [6.Bodor D.L. al.Of shapes motion: basis animal migration.Dev. 550-562Abstract (45) Scholar,7.Yamada K.M. Sixt M. Mechanisms migration.Nat. Rev. Mol. Cell Biol. 2019; 20: 738-752Crossref (262) lobopodial cross-linked linearly elastic spatially confined intracellular pressure, cortical actin flow, ion fluxes, [8.Zhao R. al.Cell sensing decision-making confinement: role TRPM7 tug war hydraulic pressure cross-sectional area.Sci. Adv. 5eaaw7243Crossref (35) Scholar, 9.Patel S. al.Myosin II Arp2/3 cross-talk governs lamellipodia formation.Mol. 32: 579-589Crossref 10.Ullo M.F. Logue J.S. ADF cofilin-1 collaborate promote flow leader bleb-based cells.eLife. 10e67856Crossref (6) 11.Reversat A. al.Cellular locomotion environmental topography.Nature. 582: 582-585Crossref (69) 12.Yolland L. al.Persistent polarized global essential directionality 21: 1370-1381Crossref (22) Scholar].The microarchitecture affect differentiation [13.Doyle A.D. al.Local microenvironment through spatiotemporal dynamics contractility-dependent adhesions.Nat. 2015; 6: 8720Crossref (268) Scholar,14.Seo B.R. al.Collagen mechanically controls myofibroblast differentiation.Proc. Natl. Acad. Sci. U. 117: 11387-11398Crossref (58) For example, networks, fiber thickness pore size, adipose stromal toward process independent overall stiffness previously known stem [14.Seo Scholar,15.Chaudhuri O. al.Effects cellular behaviour.Nature. 584: 535-546Crossref (427) Scholar].Matrix propertiesThe local migratory speed show differences molecular elasticity [15.Chaudhuri Examining whether an soft stiff numerous previous [16.Hayward M.K. al.Tissue mechanics fate, cancer.Dev. 56: 1833-1847Abstract (20) Scholar,17.Xue B. al.Engineering hydrogels homogeneous controlling lineage specification.Proc. 118e2110961118Crossref (13) Scholar] ideally be complemented behavior environments differing viscoelasticity. reason biological matrices often viscoelastic, they display combination viscosity thick fluid attempts return material original form deforming force released. results plastic deformation slipping, creep 'stress relaxation' response deformed, without returning form. Viscoelasticity modulated extent crosslinking property effects behavior, although underlying yet clear. altered rheology filopodial versus protrusions leading edge cell, rates spreading migration, processes morphogenesis, epithelial-mesenchymal transition, invasion, [18.Adebowale K. al.Enhanced substrate stress relaxation promotes filopodia-mediated Mater. 1290-1299Crossref (36) 19.Gong Z. al.Matching timescales maximizes viscoelastic substrates.Proc. 115: E2686-E2695Crossref (129) 20.Wisdom al.Matrix plasticity confining microenvironments.Nat. 9: 4144Crossref (162) 21.Yang mechanosensing synthetic controlled biophysical dynamics.Nat. 3514Crossref 22.Indana al.Viscoelasticity adhesion biomaterials control pluripotent morphogenesis culture.Adv. 33e2101966Crossref (17) 23.Chang A.C. al.Precise tuning characterization interfaces study early transition behaviors.Langmuir. 2022; (Published online February 10, 2022)https://doi.org/10.1021/acs.langmuir.1c03048Crossref (3) 24.Hui E. al.The combined influence adhesive cues fibroblast organization.Cell. Bioeng. 14: 427-440Crossref (9) fact chemical substantially alter mode, speed, means one cannot simply 'work 3D' due factors An ongoing challenge will generate accurately mimic specific use ex tissues. Development physiological simple gels current valuable accurate platforms testing translational approaches.MechanotransductionDifferent elicit distinct responses cells. 2D revealed test repetitively probing [25.Plotnikov S.V. al.Force fluctuations within mediate ECM-rigidity directed migration.Cell. 2012; 151: 1513-1527Abstract (559) analogous hikers footing when crossing unstable terrain. Cells sense respond ECM-transmitted forces tension involves integrin-based where actomyosin-mediated transmitted substrata [26.Zuidema al.Crosstalk complexes mechanotransduction.Bioessays. 42e2000119Crossref (31) Scholar,27.Doyle al.Cell-extracellular dynamics.Phys. 19https://doi.org/10.1088/1478-3975/ac4390Crossref (8) In environments, mechanotransduction level resembles under conditions stiffer substrates stabilize while softer, flexible shorter lifetimes faster Scholar].Mechanotransduction becomes particularly concerning cycle. evidence fibroblasts migrating reveals prior translocation, initially deform (prestrain) fibrils, increasing self-generated contracting transmitting essentially first 'pulling up slack rope' (i.e., fibrils [28.Doyle al.3D anterior contraction generates prestrain.Dev. 826-841.e4Abstract Scholar]). Interestingly, epithelial relatively equal-and-opposite strain transmission posterior directions 2A ) [29.Hall M.S. al.Fibrous nonlinear enables positive ECMs.Proc. 2016; 113: 14043-14048Crossref (174) (nonepithelial) cancers constant prestrains twofold greater front rear suggesting disconnect propagation 2A) prestrain likely genetically primed contractility-centric mode higher expression myosin II) enhanced microenvironment. sequence events distinctive, actomyosin contractions preceding leading-edge protrusive activity, helps establish unique cycle 2B–C) Discrepancies cycles importance conditions.Figure 2Mechanotransduction migration.Show full caption(A) Schematic showing directionally gels. Mesenchymal (left) high extensive integrin ligation large strains larger rear. Similar attributes seen fibrosarcoma cells, majority (right) smaller, transient rear, lower graph summarizing latter concept, requires further testing). (B C) schematic shows matrix. Yellow arrows depict directional applied matrix, magenta indicate relative summed given region. During cycle, (C) retrograde pull stabilizes (gray ovals) edge. A contralateral anterograde (increased direction migration) leads pinching followed increase protrusion (broken white line). Abbreviation: matrix.View Large Image Figure ViewerDownload Hi-res image Download (PPT)In addition, (elastic etc.) alters mechanotransduction. suggest ECMs Viscoelastic effective eliciting compared Future evaluate interacting properties, vitro microenvironments.The nucleus migrationSome 'nuclear piston' pulled anteriorly contractility pressurize drive 'lobopodial' forward [30.Petrie R.J. al.Activating nuclear piston mechanism tumor cells.J. 2017; 216: 93-100Crossref (63) (plastic), mechanosensitive channels generated elevated hydrostatic triggering channel activation; resulting influx sodium calcium ions enhances osmotic provides additional extending promoting efficient [31.Lee H.P. activates paths microenvironments.Sci. 7eabd4058Google Scholar].Another intriguing finding stiff, bulky ruler help choice wider, readily traversed passageway [32.Renkawitz al.Nuclear positioning facilitates along path least resistance.Nature. 568: 546-550Crossref (125) Scholar,33.Lomakin A.J. acts tailoring spatial constraints.Science. 370eaba2894Crossref (110) Besides serving ruler, conjunction cytoskeleton function, gauge activate epigenetic pathways 3) Scholar,34.Venturini measures shape proprioception behavior.Science. 370eaba2644Crossref (102) 35.Maurer Lammerding driving force: disease.Annu. Biomed. Eng. 443-468Crossref (80) 36.Alisafaei F. al.Regulation architecture, mechanics, nucleocytoplasmic shuttling geometric constraints.Proc. 116: 13200-13209Crossref (82) Scholar].Figure 3Multiple mechanosensing, mechanotransduction.Show captionThe nucleus, largest organelle, function entry narrow spaces channels. contraction, thereby termed lobopodia. serve sensor responding confinement. Finally, signal transducer initiating gene expression.View (PPT)Cancer dynamicsCancer invasion continues another very active investigation various ECM. Before malignant invade interstitial tissues, must usually breach barrier surrounds 4). Although proteases degrade protease-independent breaching occur. Physical extension penetrate expand holes ATP production Caenorhabditis elegans [37.Kelley L.C. al.Adaptive F-actin polymerization localized absence MMPs.Dev. 48: 313-328.e8Abstract Human nonproteolytic repetitive microspikes widen filopodia enlarging perforations; protruding subsequently probe [38.Chang Chaudhuri Beyond proteases: invasion.J. 218: 2456-2469Crossref 39.Eschenbruch al.From fibers: remodeling acini drives II-mediated invasion.Cells. 10: 1979Crossref 40.Gong al.Recursive dissipation chemo-mechanical oscillatory invadopodia.Cell 35109047Abstract Cellular metabolic activation important successful crosstalk Scholar,41.Zanotelli M.R. al.Mechanoresponsive metabolism metastasis.Cell Metab. 33: 1307-1321Abstract 42.Romani P. metabolism.Nat. 22: 22-38Crossref (94) 43.Torrino al.Mechano-induced microtubule glutamylation 1342-1357.e10Abstract (18) 4Different membrane.Show captionCancer transiently barriers mechanisms. proteases, metalloproteinases (MMPs), locally, MMPs tips invadopodia. Even if inhibited, tiny perforations requiring energy (orange shading) (yellow arrows) push laterally ridge around expanding hole (red mounds). both processes, proteolysis perforations.View (PPT)Although generation thought involve contractility, relationship levels nonmuscle invasiveness complex. Some isoforms actomyosin-associated predicted facilitate others decreased consistent suppressor Scholar,44.Parajon mechanobiome: goldmine therapeutics.Am. Physiol. 320: C306-C323Crossref Scholar,45.Picariello H.S. IIA suppresses glioblastoma sensitive manner.Proc. 15550-15559Crossref (25) bifunctional complexity myosin-X enhancing suppressing modulating [46.Peuhu al.Myosin-X-dependent limits invasion.bioRxiv. October 22, 2021)https://doi.org/10.1101/2021.10.22.464987Google Scholar].Although obvious source disrupting structure breaching, contributor lateral branches density [47.Papalazarou Maches

Language: Английский

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Biomaterials to enhance stem cell transplantation

Cell stem cell, Journal Year: 2022, Volume and Issue: 29(5), P. 692 - 721

Published: April 27, 2022

Language: Английский

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Force- and cell state–dependent recruitment of Piezo1 drives focal adhesion dynamics and calcium entry

Science Advances, Journal Year: 2022, Volume and Issue: 8(45)

Published: Nov. 9, 2022

Mechanosensing is an integral part of many physiological processes including stem cell differentiation, fibrosis, and cancer progression. Two major mechanosensing systems-focal adhesions mechanosensitive ion channels-can convert mechanical features the microenvironment into biochemical signals. We report here unexpectedly that calcium-permeable channel Piezo1, previously perceived to be diffusive on plasma membranes, binds matrix in a force-dependent manner, promoting spreading, adhesion dynamics, calcium entry normal but not most cells tested except some glioblastoma lines. A linker domain Piezo1 needed for binding adhesions, overexpression blocks decreasing size spread area. Thus, we suggest unidentified component focal nontransformed catalyzes maturation growth through signaling, this function absent cells.

Language: Английский

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The significant role of amino acid metabolic reprogramming in cancer

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: July 29, 2024

Amino acid metabolism plays a pivotal role in tumor microenvironment, influencing various aspects of cancer progression. The metabolic reprogramming amino acids cells is intricately linked to protein synthesis, nucleotide modulation signaling pathways, regulation cell metabolism, maintenance oxidative stress homeostasis, and epigenetic modifications. Furthermore, the dysregulation also impacts microenvironment immunity. can act as molecules that modulate immune function tolerance within reshaping anti-tumor response promoting evasion by cells. Moreover, influence behavior stromal cells, such cancer-associated fibroblasts, regulate ECM remodeling promote angiogenesis, thereby facilitating growth metastasis. Understanding intricate interplay between crucial significance. Expanding our knowledge multifaceted roles holds significant promise for development more effective therapies aimed at disrupting dependencies modulating enhance responses inhibit

Language: Английский

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Nanoscale distribution of bioactive ligands on biomaterials regulates cell mechanosensing through translocation of actin into the nucleus

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(10)

Published: March 5, 2025

Cells respond to adhesive ligands such as arginine-glycine-aspartate (RGD) through integrins, which regulates cellular activities via influencing cytoskeleton assembly. Herein, we report that the nanoscale distribution of active on biomaterials cells not only cytoplasmic tension but also nuclear tension. This is particularly related translocation actin into nucleus and highlighted in our interpretation an "abnormal" phenomenon large RGD nanospacing (>70 nm) disassembles integrin clusters, inhibits cell adhesion, promotes osteogenic differentiation mesenchymal stem cells. Our studies reveal unstable adhesion at 150 nm distance increases dynamics, resulting globular (G) actin. The compartment polymerization more G-actins filamentous actins tension, facilitating transcription activity releasing calcium ions from endoplasmic reticulum. noncanonical mechanotransduction process sheds insight pertinent cell-material interactions.

Language: Английский

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Can’t handle the stress? Mechanobiology and disease

Trends in Molecular Medicine, Journal Year: 2022, Volume and Issue: 28(9), P. 710 - 725

Published: June 15, 2022

Language: Английский

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