bims-ecemfi Biomed News
on ECM and fibroblasts
Issue of 2024–11–24
eight papers selected by
Badri Narayanan Narasimhan, University of California, San Diego
  1. Chromatin compaction during confined cell migration induces and reshapes nuclear condensates.
  2. Matrix stiffness drives drop like nuclear deformation and lamin A/C tension-dependent YAP nuclear localization.
  3. Matrix Architecture and Mechanics Regulate Myofibril Organization, Costamere Assembly, and Contractility in Engineered Myocardial Microtissues.
  4. Physiological mechanical forces accelerate the degradation of bovine lung collagen fibers by bacterial collagenase.
  5. Mechanical confinement matters: Unveiling the effect of two-photon polymerized 2.5D and 3D microarchitectures on neuronal YAP expression and neurite outgrowth.
  6. High-Resolution Atomic Force Microscopy Investigation of Alginate Hydrogel Materials in Aqueous Media.
  7. An alternative route for β-hydroxybutyrate metabolism supports fatty acid synthesis in cancer cells.
  8. Modeling collagen fibril degradation as a function of matrix microarchitecture.
  1. Nat Commun. 2024 Nov 18. 15(1): 9964
    Chromatin compaction during confined cell migration induces and reshapes nuclear condensates.
    Jessica Z Zhao, Jing Xia, Clifford P Brangwynne.
      Cell migration through small constrictions during cancer metastasis requires significant deformation of the nucleus, with associated mechanical stress on the nuclear lamina and chromatin. However, how mechanical deformation impacts various subnuclear structures, including protein and nucleic acid-rich biomolecular condensates, is largely unknown. Here, we find that cell migration through confined spaces gives rise to mechanical deformations of the chromatin network, which cause embedded nuclear condensates, including nucleoli and nuclear speckles, to deform and coalesce. Chromatin deformations exhibit differential behavior in the advancing vs. trailing region of the nucleus, with the trailing half being more permissive for de novo condensate formation. We show that this results from increased chromatin heterogeneity, which gives rise to a shift in the binodal phase boundary. Taken together, our findings show how chromatin deformation impacts condensate assembly and properties, which can potentially contribute to cellular mechanosensing.
    DOI:  https://doi.org/10.1038/s41467-024-54120-5
  2. Nat Commun. 2024 Nov 22. 15(1): 10151
    Matrix stiffness drives drop like nuclear deformation and lamin A/C tension-dependent YAP nuclear localization.
    Ting-Ching Wang, Samere Abolghasemzade, Brendan P McKee, Ishita Singh, Kavya Pendyala, Mohammad Mohajeri, Hailee Patel, Aakansha Shaji, Anna L Kersey, Kajol Harsh, Simran Kaur, Christina R Dollahon, Sasanka Chukkapalli, Pushkar P Lele, Daniel E Conway, Akhilesh K Gaharwar, Richard B Dickinson, Tanmay P Lele.
      Extracellular matrix (ECM) stiffness influences cancer cell fate by altering gene expression. Previous studies suggest that stiffness-induced nuclear deformation may regulate gene expression through YAP nuclear localization. We investigated the role of the nuclear lamina in this process. We show that the nuclear lamina exhibits mechanical threshold behavior: once unwrinkled, the nuclear lamina is inextensible. A computational model predicts that the unwrinkled lamina is under tension, which is confirmed using a lamin tension sensor. Laminar unwrinkling is caused by nuclear flattening during cell spreading on stiff ECM. Knockdown of lamin A/C eliminates nuclear surface tension and decreases nuclear YAP localization. These findings show that nuclear deformation in cells conforms to the nuclear drop model and reveal a role for lamin A/C tension in controlling YAP localization in cancer cells.
    DOI:  https://doi.org/10.1038/s41467-024-54577-4
  3. Adv Sci (Weinh). 2024 Nov 18. e2309740
    Matrix Architecture and Mechanics Regulate Myofibril Organization, Costamere Assembly, and Contractility in Engineered Myocardial Microtissues.
    Samuel J DePalma, Javiera Jilberto, Austin E Stis, Darcy D Huang, Jason Lo, Christopher D Davidson, Aamilah Chowdhury, Robert N Kent, Maggie E Jewett, Hiba Kobeissi, Christopher S Chen, Emma Lejeune, Adam S Helms, David A Nordsletten, Brendon M Baker.
      The mechanical function of the myocardium is defined by cardiomyocyte contractility and the biomechanics of the extracellular matrix (ECM). Understanding this relationship remains an important unmet challenge due to limitations in existing approaches for engineering myocardial tissue. Here, they established arrays of cardiac microtissues with tunable mechanics and architecture by integrating ECM-mimetic synthetic, fiber matrices, and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), enabling real-time contractility readouts, in-depth structural assessment, and tissue-specific computational modeling. They found that the stiffness and alignment of matrix fibers distinctly affect the structural development and contractile function of pure iPSC-CM tissues. Further examination into the impact of fibrous matrix stiffness enabled by computational models and quantitative immunofluorescence implicates cell-ECM interactions in myofibril assembly, myofibril maturation, and notably costamere assembly, which correlates with improved contractile function of tissues. These results highlight how iPSC-CM tissue models with controllable architecture and mechanics can elucidate mechanisms of tissue maturation and disease.
    Keywords:  biomaterials; cardiac tissue engineering; cardiomyocytes; electrospinning; extracellular matrix; induced pluripotent stem cells; mechanosensing
    DOI:  https://doi.org/10.1002/advs.202309740
  4. Sci Rep. 2024 Nov 22. 14(1): 29008
    Physiological mechanical forces accelerate the degradation of bovine lung collagen fibers by bacterial collagenase.
    Yuqing Deng, Jacob Herrmann, Yu Wang, Minh Nguyen, Joseph K Hall, Jae Hun Kim, Michael L Smith, Kenneth R Lutchen, Elizabeth Bartolák-Suki, Béla Suki.
      Collagen fibers, one of the key load-bearing components of the extracellular matrix, contribute significantly to tissue integrity through their mechanical properties of strain-dependent stiffening. This study investigated the effects of bacterial collagenase on the mechanical behavior of individual bovine lung collagen fibers in the presence or absence of mechanical forces, with a focus on potential implications for emphysema, a condition associated with collagen degradation and alveolar wall rupture. Tensile tests were conducted on individual collagen fibers isolated from bovine lung tissue. The rate of degradation was characterized by the change in fiber Young's modulus during 60 min of digestion under various mechanical conditions mimicking the mechanical stresses on the fibers during breathing. Compared to digestion without mechanical forces, a significantly larger drop of fiber modulus was observed in the presence of static or intermittent mechanical forces. Fiber yield stress was also reduced after digestion indicating compromised fiber failure. By incorporating fibril waviness obtained by scanning electron microscopic images, an analytic model allowed estimation of fibril modulus. A computational model that incorporated waviness and the results of tensile tests was also developed to simulate and interpret the data. The simulation results provided insights into the mechanical consequences of bacterial collagenase and mechanical forces on collagen fibers, revealing both fibril softening and rupture during digestion. These findings shed light on the microscale changes in collagen fiber structure and mechanics under enzymatic digestion and breathing-like mechanical stresses with implications for diseases that are impacted by collagen degradation such as emphysema.
    Keywords:  Computational model; Fiber modulus; Fibril modulus; Tensile testing; Waviness
    DOI:  https://doi.org/10.1038/s41598-024-77704-z
  5. Mater Today Bio. 2024 Dec;29 101325
    Mechanical confinement matters: Unveiling the effect of two-photon polymerized 2.5D and 3D microarchitectures on neuronal YAP expression and neurite outgrowth.
    Ahmed Sharaf, Jean-Philippe Frimat, Angelo Accardo.
      The effect of mechanical cues on cellular behaviour has been reported in multiple studies so far, and a specific aspect of interest is the role of mechanotransductive proteins in neuronal development. Among these, yes-associated protein (YAP) is responsible for multiple functions in neuronal development such as neuronal progenitor cells migration and differentiation while myocardin-related transcription factor A (MRTFA) facilitates neurite outgrowth and axonal pathfinding. Both proteins have indirectly intertwined fates via their signalling pathways. There is little literature investigating the roles of YAP and MRTFA in vitro concerning neurite outgrowth in mechanically confined microenvironments. Moreover, our understanding of their relationship in immature neurons cultured within engineered confined microenvironments is still lacking. In this study, we fabricated, via two-photon polymerization (2PP), 2.5D microgrooves and 3D polymeric microchannels, with a diameter range from 5 to 30 μm. We cultured SH-SY5Y cells and differentiated them into immature neuron-like cells on both 2.5D and 3D microstructures to investigate the effect of mechanical confinement on cell morphology and protein expression. In 2.5D microgrooves, both YAP and MRTFA nuclear/cytoplasmic (N/C) ratios exhibited maxima in the 10 μm grooves indicating a strong relation with mechanical-stress-inducing confinement. In 3D microchannels, both proteins' N/C ratio exhibited minima in presence of 5 or 10 μm channels, a behaviour that was opposite to the ones observed in the 2.5D microgrooves and that indicates how the geometry and mechanical confinement of 3D microenvironments are unique compared to 2.5D ones due to focal adhesion, actin, and nuclear polarization. Further, especially in presence of 2.5D microgrooves, cells featured an inversely proportional relationship between YAP N/C ratio and the average neurite length. Finally, we also cultured human induced pluripotent stem cells (hiPSCs) and differentiated them into cortical neurons on the microstructures for up to 2 weeks. Interestingly, YAP and MRTFA N/C ratios also showed a maximum around the 10 μm 2.5D microgrooves, indicating the physiological relevance of our study. Our results elucidate the possible differences induced by 2.5D and 3D confining microenvironments in neuronal development and paves the way for understanding the intricate interplay between mechanotransductive proteins and their effect on neural cell fate within engineered cell microenvironments.
    DOI:  https://doi.org/10.1016/j.mtbio.2024.101325
  6. Langmuir. 2024 Nov 18.
    High-Resolution Atomic Force Microscopy Investigation of Alginate Hydrogel Materials in Aqueous Media.
    Yunbo Zheng, Umit Celik, Charlotte Vorwald, J Kent Leach, Gang-Yu Liu.
      Alginate hydrogels are frequently used in 3D bioprinting and tissue repair and regeneration. Establishing the structure-property-performance correlation of these materials would benefit significantly from high-resolution structural characterization in aqueous environments from the molecular level to continuum. This study overcomes technical challenges and enables high-resolution atomic force microscopy (AFM) imaging of hydrated alginate hydrogels in aqueous media. By combining a new sample preparation protocol with extremely gentle tapping mode AFM imaging, we characterized the morphology and regional mechanical properties of the hydrated alginate. Upon cross-linking, basic units of these hydrogel materials consist of egg-box dimers, which assemble into long fibrils. These fibrils congregate and pile up, forming a sponge-like structure, whose pore size and distribution depend on the cross-linking conditions. At the exterior, surface tension impacts the piling of fibrils, leading to stripe-like features. These structural features contribute to local, regional, and macroscopic mechanics. The outcome provides new insights into its structural characteristics from nanometers to tens of micrometers, i.e., at the dimensions pertaining to biomaterial and hydrogel-cell interactions. Collectively, the results advance our knowledge of the structure and mechanics from the nanometer to continuum, facilitating advanced applications in hydrogel biomaterials.
    DOI:  https://doi.org/10.1021/acs.langmuir.4c03554
  7. bioRxiv. 2024 Nov 03. pii: 2024.10.31.621317. [Epub ahead of print]
    An alternative route for β-hydroxybutyrate metabolism supports fatty acid synthesis in cancer cells.
    Faith C Kaluba, Thomas J Rogers, Yu-Jin Jeong, Althea Waldhart, Kelly H Sokol, Cameron J Lee, Samuel R Daniels, Joseph Longo, Amy Johnson, Ryan D Sheldon, Russell G Jones, Evan C Lien.
      Cancer cells are exposed to diverse metabolites in the tumor microenvironment that are used to support the synthesis of nucleotides, amino acids, and lipids needed for rapid cell proliferation 1-3 . Recent work has shown that ketone bodies such as β-hydroxybutyrate (β-OHB), which are elevated in circulation under fasting conditions or low glycemic diets, can serve as an alternative fuel that is metabolized in the mitochondria to provide acetyl-CoA for the tricarboxylic acid (TCA) cycle in some tumors 4-7 . Here, we discover a non-canonical route for β-OHB metabolism, in which β-OHB can bypass the TCA cycle to generate cytosolic acetyl-CoA for de novo fatty acid synthesis in cancer cells. We show that β-OHB-derived acetoacetate in the mitochondria can be shunted into the cytosol, where acetoacetyl-CoA synthetase (AACS) and thiolase convert it into acetyl-CoA for fatty acid synthesis. This alternative metabolic routing of β-OHB allows it to avoid oxidation in the mitochondria and net contribute to anabolic biosynthetic processes. In cancer cells, β-OHB is used for fatty acid synthesis to support cell proliferation under lipid-limited conditions in vitro and contributes to tumor growth under lipid-limited conditions induced by a calorie-restricted diet in vivo . Together, these data demonstrate that β-OHB is preferentially used for fatty acid synthesis in cancer cells to support tumor growth.
    DOI:  https://doi.org/10.1101/2024.10.31.621317
  8. Soft Matter. 2024 Nov 18.
    Modeling collagen fibril degradation as a function of matrix microarchitecture.
    Bhanjan Debnath, Badri Narayanan Narasimhan, Stephanie I Fraley, Padmini Rangamani.
      Collagenolytic degradation is a process fundamental to tissue remodeling. The microarchitecture of collagen fibril networks changes during development, aging, and disease. Such changes to microarchitecture are often accompanied by changes in matrix degradability. In a matrix, the pore size and fibril characteristics such as length, diameter, number, orientation, and curvature are the major variables that define the microarchitecture. In vitro, collagen matrices of the same concentration but different microarchitectures also vary in degradation rate. How do different microarchitectures affect matrix degradation? To answer this question, we developed a computational model of collagen degradation. We first developed a lattice model that describes collagen degradation at the scale of a single fibril. We then extended this model to investigate the role of microarchitecture using Brownian dynamics simulation of enzymes in a multi-fibril three dimensional matrix to predict its degradability. Our simulations predict that the distribution of enzymes around the fibrils is non-uniform and depends on the microarchitecture of the matrix. This non-uniformity in enzyme distribution can lead to different extents of degradability for matrices of different microarchitectures. Our simulations predict that for the same enzyme concentration and collagen concentration, a matrix with thicker fibrils degrades more than that with thinner fibrils. Our model predictions were tested using in vitro experiments with synthetic collagen gels of different microarchitectures. Experiments showed that indeed degradation of collagen depends on the matrix architecture and fibril thickness. In summary, our study shows that the microarchitecture of the collagen matrix is an important determinant of its degradability.
    DOI:  https://doi.org/10.1039/d4sm00971a
This page is being maintained by Thomas Krichel. It was last updated on 2025‒03‒30 at 1:59.