bims-ecemfi Biomed News
on ECM and fibroblasts
Issue of 2026–09–27
six papers selected by
Badri Narayanan Narasimhan, University of California, San Diego
  1. Matrix Stiffness Regulates Mechanotransduction and Vascular Network Formation of hiPSC-Derived Endothelial Progenitors Encapsulated in 3D Hydrogels.
  2. Load-dependent RGD-context sensing via αV-class integrins reprograms cell adhesion and mechanics.
  3. Substrate curvature and stiffness equivalence in governing cell mechanosensing.
  4. Mechanical polarity links adhesion-regulated protrusions to directional stability in glioblastoma cell migration.
  5. Extracellular-matrix mediated stresses spatially bias myoblast fusion and myotube growth.
  6. Matrix viscoelasticity amplifies pro-fibrotic crosstalk between cardiac fibroblasts and macrophages.
  1. ACS Biomater Sci Eng. 2026 Sep 24.
    Matrix Stiffness Regulates Mechanotransduction and Vascular Network Formation of hiPSC-Derived Endothelial Progenitors Encapsulated in 3D Hydrogels.
    Jiwan Han, Kathleen Halwachs, Toni West, Bryce Larsen, Michael S Sacks, Adrianne M Rosales, Janet Zoldan.
      Matrix mechanics are central to vasculogenesis, yet stiffness is often confounded with ligand density or degradability in common hydrogel platforms. Here, we use norbornene-modified hyaluronic acid (NorHA) hydrogels to independently tune stiffness within a sub-kilopascal range (190-884 Pa) relevant to embryonic vascular development and assess how stiffness regulates self-assembly of human iPSC-derived endothelial progenitors (hiPSC-EPs) into vascular networks, focusing on temporal dynamics of cellular mechanotransduction and contractility, leading to matrix displacement. EPs in intermediate-stiffness hydrogels (∼551 Pa) displayed the highest cell volume and surface area, increased nuclear Yes-associated protein (YAP), and elevated upstream phosphorylated focal adhesion kinase (pFAK), consistent with enhanced mechanotransduction signaling. However, despite high vinculin and pFAK expression, cells at this stiffness condition failed to form a robust, interconnected plexus. In contrast, the most compliant hydrogels (∼190 Pa) supported the most interconnected plexus assembly despite lower nuclear YAP, vinculin, and pFAK expression. ROCK inhibition reduced nuclear YAP, vinculin, and pFAK, confirming tension-dependent regulation, but did not rescue vasculogenesis at 551 Pa and instead impaired network formation at 190 Pa. Importantly, 3D traction microscopy revealed that hiPSC-EPs displayed the highest matrix displacement at this lowest storage modulus, suggesting that cell-generated traction forces and matrix deformability synergistically facilitate vascular morphogenesis. These results suggest that the plexus formation is promoted by matrix compliance that permits matrix displacement, rather than by elevated YAP-mediated mechanotransduction alone. Together, these findings establish a mechanically tunable framework to guide the design of next-generation hydrogels for therapeutic vascular regeneration.
    Keywords:  actomyosin contractility; focal adhesion dynamics; hiPSC-derived endothelial progenitors; matrix stiffness; mechanotransduction; vascular morphogenesis
    DOI:  https://doi.org/10.1021/acsbiomaterials.6c00563
  2. Nat Commun. 2026 Aug 24. pii: 10137. [Epub ahead of print]17(1):
    Load-dependent RGD-context sensing via αV-class integrins reprograms cell adhesion and mechanics.
    Upnishad Sharma, Jakob M Reber, Jonne Helenius, Cara Buchholz, Reinhard Fässler, Nico Strohmeyer, Daniel J Müller.
      The biochemical and mechanical properties of extracellular matrix proteins govern cell adhesion, mechanics, and migration. How cells use integrins to discriminate between the arginine-glycine-aspartic acid motifs presented by different extracellular matrix proteins, a process central to tissue homeostasis and disease, has remained unclear. Here we show that mammalian cells mount a distinct "biphasic" mechanical response through αV-class integrins to the arginine-glycine-aspartic acid motif of vitronectin compared with fibronectin, osteopontin, and cyclic arginine-glycine-aspartic acid. Within seconds of contact with vitronectin, we find that αV-class integrins strengthen cell adhesion through two load-dependent mechanotransduction pathways in which αVβ3 and αVβ5 integrins take complementary roles. Under low load, we demonstrate that the first phase requires both integrins together with an intact, pre-tensed actomyosin cortex, talin, paxillin, and focal adhesion kinase activity, with αVβ5 integrin additionally engaging clathrin-mediated endocytosis. Under higher load, we show that the second phase is dominated by αVβ3 integrin-directed actin-related protein 2/3, cellular Src kinase, and phosphatidyl inositol-3-kinase signaling, which organizes the consensus adhesome, while αVβ5 integrin concurrently drives cellular stiffening. Taken together, we find that αV-class integrins rapidly deploy arginine-glycine-aspartic acid -motif- and β-subunit-specific programs that cooperatively tune cell adhesion and mechanics according to the extracellular matrix composition.
    DOI:  https://doi.org/10.1038/s41467-026-77028-8
  3. Nat Commun. 2026 Aug 25. pii: 10141. [Epub ahead of print]17(1):
    Substrate curvature and stiffness equivalence in governing cell mechanosensing.
    Crescenzo Frascogna, Valeria Panzetta, Valentina Mollo, Raffaele Marotta, Salvatore Strano, Sabato Fusco, Paolo A Netti.
      Mechanosensing enables cells to perceive and interpret their mechanical microenvironment, including forces, stiffness and topography. Although focal adhesions (FAs) are central to this process, their structural adaptation to mechanical stimuli remains poorly understood. Here, we uncover FA tilting - the inclination of the FA plane relative to the substrate - as a mechanically regulated architectural feature. Using reverse cell imprinting and atomic force microscopy, we reveal a strong inverse correlation between FA tilting angle and substrate stiffness. A two-dimensional clutch model shows that tilting emerges from force distribution across the FA-substrate interface and contributes to cell mechanosensing. By engineering rigid substrates with defined curvatures, we impose specific tilting angles independently of stiffness and modulate the cellular mechanostate, revealing a curvature-stiffness mechanical equivalence principle. This enables the construction of a correlation map linking curvature values to equivalent stiffness levels.Together, our results identify FA tilting as a geometrical and mechanical transducer and a powerful design parameter for instructive biomaterials in physio-pathological tissue engineering.
    DOI:  https://doi.org/10.1038/s41467-026-76866-w
  4. PLoS Comput Biol. 2026 Sep;22(9): e1014772
    Mechanical polarity links adhesion-regulated protrusions to directional stability in glioblastoma cell migration.
    Haruna Tagawa, Daisuke Kanematsu, Asako Katsuma, Naoyuki Inagaki, Yonehiro Kanemura, Yuichi Sakumura.
      Glioblastoma invasion critically limits therapeutic outcomes, yet the physical principles that govern directional cell migration remain poorly understood. In particular, the degree to which protrusive forces are aligned or cancel each other, and how this governs migration efficiency, have remained unquantified. Here, we introduce mechanical polarity, a quantitative descriptor that captures the alignment of protrusive and adhesive forces driving migration. By integrating time-lapse imaging of the glioblastoma-derived cells with a coarse-grained biophysical model incorporating catch- and slip-bond kinetics, we analyzed motility on fibronectin- and laminin-coated substrates. In our model, the extracellular matrix (ECM) is treated as an external boundary condition that modulates adhesion dynamics, distinct from intrinsic cellular mechanics. We demonstrate that while protrusive activity remains similar across environments, the fibronectin-fitted model exhibited less stable effective adhesion dynamics that led to poorly coordinated protrusions and significant force cancellation, thereby reducing net displacement. These differences are not fully captured by conventional descriptors of protrusion activity but are reflected in mechanical polarity. Conversely, laminin promotes stable adhesions and the alignment of protrusive forces, a state characterized by high mechanical polarity. Our results support mechanical polarity as a candidate physical descriptor linking molecular adhesion kinetics to cell-scale migration stability. This framework provides a quantitative basis for understanding force coordination in glioblastoma cell motility and offers a physical basis for strategies to suppress invasive behavior.
    DOI:  https://doi.org/10.1371/journal.pcbi.1014772
  5. Nat Commun. 2026 Aug 22. pii: 10057. [Epub ahead of print]17(1):
    Extracellular-matrix mediated stresses spatially bias myoblast fusion and myotube growth.
    Yoann Le Toquin, Sushil Dubey, Aleksandra Ardaševa, Lakshmi Balasubramaniam, Emilie Delaune, Valérie Morin, Amin Doostmohammadi, Christophe Marcelle, Benoît Ladoux.
      Myoblast fusion into multinucleated myotubes is essential for skeletal muscle development and repair, yet how tissue-scale mechanics contributes to this process remains poorly understood. Here, we show that primary myoblasts behave as an evolving active nematic system in which actomyosin-dependent stresses, extracellular-matrix (ECM) remodeling and fusion-driven myotube growth are dynamically coupled. As myoblasts fuse into elongated myotubes, orientational order increases and the nematic field is progressively reshaped. We identify a strong coupling between cellular and ECM nematic organization, whereby cytoskeleton-dependent ECM remodeling stabilizes topological defects and reinforces their associated stress patterns. Fusion events preferentially accumulate near comet-shaped +1/2 defects, which correspond to regions of high compressive stress predicted by our theoretical model. Our findings support a model in which the intrinsic fusion machinery provides fusion competence, while ECM-stabilized nematic stress patterns spatially bias the localization of fusion events. Fusion-driven myotube growth then feeds back on the mechanical landscape, increasing nematogen length and stress magnitude. Together, these results reveal a self-reinforcing biomechanical mechanism that contributes to the organization of myoblast fusion and myotube growth, with potential relevance for developmental and regenerative morphogenesis.
    DOI:  https://doi.org/10.1038/s41467-026-76967-6
  6. Cell Rep. 2026 Sep 24. pii: S2211-1247(26)01119-8. [Epub ahead of print]45(10): 118041
    Matrix viscoelasticity amplifies pro-fibrotic crosstalk between cardiac fibroblasts and macrophages.
    Hamza Atcha, Carrie T Bishop, Thomas G Molley, Abhinaba Banerjee, Alis Balayan, Adam J Engler.
      Cardiac fibrosis is driven by dynamic crosstalk between cardiac fibroblasts and macrophages, yet how tissue mechanics regulate these interactions remains poorly defined. Here, we introduce a viscoelastic coculture platform that enables precise interrogation of mechanical and paracrine signaling in a physiologically relevant context. Counterintuitively, we found that soft, viscous environments promote human-induced pluripotent stem cell-derived cardiac fibroblast activation and macrophage healing phenotypes, while stiff environments bias macrophages toward inflammation. Coculture in soft, viscous matrices amplifies reciprocal pro-fibrotic signaling, while sequential exposure to inflammatory and then healing macrophages, which mimic in vivo dynamics, further exacerbates fibroblast activation. Mechanistically, we identified a STAT1 and AP-1 mediated, viscoelasticity-driven positive feedback loop involving inflammatory cytokines IL6, CCL5, and CCL2 as well as healing cytokines VEGFA and CTGF. This work establishes tissue viscoelasticity as a central regulator of immune-stromal interactions and provides a broadly applicable platform for dissecting mechanobiological drivers of fibrosis.
    Keywords:  CP: cell biology; biomaterials; cardiac fibroblasts; inflammation; macrophage; mechanics
    DOI:  https://doi.org/10.1016/j.celrep.2026.118041
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