bims-ecemfi Biomed News
on ECM and fibroblasts
Issue of 2024–11–03
thirteen papers selected by
Badri Narayanan Narasimhan, University of California, San Diego
  1. Direct M2 macrophage co-culture overrides viscoelastic hydrogel mechanics to promote fibroblast activation.
  2. Molecular counting of myosin force generators in growing filopodia.
  3. Matrix stiffening from collagen fibril density and alignment modulates YAP-mediated T-cell immune suppression.
  4. Tuning porosity of macroporous hydrogels enables rapid rates of stress relaxation and promotes cell expansion and migration.
  5. Cellular Alignment and Matrix Stiffening Induced Changes in Human Induced Pluripotent Stem Cell Derived Cardiomyocytes.
  6. Ligand presentation controls collective MSC response to matrix stress relaxation in hybrid PEG-HA hydrogels.
  7. Cell shape and orientation control galvanotactic accuracy.
  8. Migration and proliferation drive the emergence of patterns in co-cultures of differentiating vascular progenitor cells.
  9. Stromal softness confines pancreatic cancer growth through lysosomal-cathepsin mediated YAP1 degradation.
  10. Modeling epithelial-mesenchymal transition in patient-derived breast cancer organoids.
  11. Emergent behaviors of buckling-driven elasto-active structures.
  12. Supramolecular Conductive Hydrogels for Tissue Engineering Applications.
  13. Mechano-assisted strategies to improve cancer chemotherapy.
  1. bioRxiv. 2024 Oct 15. pii: 2024.10.13.618034. [Epub ahead of print]
    Direct M2 macrophage co-culture overrides viscoelastic hydrogel mechanics to promote fibroblast activation.
    Leilani R Astrab, Mackenzie L Skelton, Steven R Caliari.
      Fibroblast activation drives fibrotic diseases such as pulmonary fibrosis. However, the complex interplay of how tissue mechanics and macrophage signals combine to influence fibroblast activation is not well understood. Here, we use hyaluronic acid hydrogels as a tunable cell culture system to mimic lung tissue stiffness and viscoelasticity. We applied this platform to investigate the influence of macrophage signaling on fibroblast activation. Fibroblasts cultured on stiff (50 kPa) hydrogels mimicking fibrotic tissue exhibit increased activation as measured by spreading as well as type I collagen and cadherin-11 expression compared to fibroblasts cultured on soft (1 kPa) viscoelastic hydrogels mimicking normal tissue. These trends were unchanged in fibroblasts cultured with macrophage-conditioned media. However, fibroblasts directly co-cultured with M2 macrophages show increased activation, even on soft viscoelastic hydrogels that normally suppress activation. Inhibition of interleukin 6 (IL6) signaling does not change activation in fibroblast-only cultures but ameliorates the pro-fibrotic effects of M2 macrophage co-culture. These results underscore the ability of direct M2 macrophage co-culture to override hydrogel viscoelasticity to promote fibroblast activation in an IL6-dependent manner. This work also highlights the utility of using hydrogels to deconstruct complex tissue microenvironments to better understand the interplay between microenvironmental mechanical and cellular cues.
    Keywords:  fibrosis; hydrogels; macrophages; mechanotransduction
    DOI:  https://doi.org/10.1101/2024.10.13.618034
  2. J Biol Chem. 2024 Oct 28. pii: S0021-9258(24)02436-0. [Epub ahead of print] 107934
    Molecular counting of myosin force generators in growing filopodia.
    Gillian N Fitz, Matthew J Tyska.
      Animal cells build actin-based surface protrusions to enable diverse biological activities, ranging from cell motility to mechanosensation to solute uptake. Long-standing models of protrusion growth suggest that actin filament polymerization provides the primary mechanical force for "pushing" the plasma membrane outward at the distal tip. Expanding on these actin-centric models, our recent studies used a chemically inducible system to establish that plasma membrane-bound myosin motors, which are abundant in protrusions and accumulate at the distal tips, can also power robust filopodial growth. How protrusion resident myosins coordinate with actin polymerization to drive elongation remains unclear, in part because the number of force generators and thus, the scale of their mechanical contributions remain undefined. To address this gap, we leveraged the SunTag system to count membrane-bound myosin motors in actively growing filopodia. Using this approach, we found that the number of myosins is log-normally distributed with a mean of 12.0 ± 2.5 motors [GeoMean ± GeoSD] per filopodium. Together with unitary force values and duty ratio estimates derived from biophysical studies for the motor used in these experiments, we calculate that a distal tip population of myosins could generate a time averaged force of ∼tens of pN to elongate filopodia. This range is comparable to the expected force production of actin polymerization in this system, a point that necessitates revision of popular physical models for protrusion growth.
    Keywords:  actin; bundle; cytoskeleton; filament; membrane; protrusion
    DOI:  https://doi.org/10.1016/j.jbc.2024.107934
  3. Biomaterials. 2024 Oct 20. pii: S0142-9612(24)00434-4. [Epub ahead of print]315 122900
    Matrix stiffening from collagen fibril density and alignment modulates YAP-mediated T-cell immune suppression.
    Jiranuwat Sapudom, Aseel Alatoom, Paul Sean Tipay, Jeremy Cm Teo.
      T-cells are essential components of the immune system, adapting their behavior in response to the mechanical environments they encounter within the body. In pathological conditions like cancer, the extracellular matrix (ECM) often becomes stiffer due to increased density and alignment of collagen fibrils, which can have a significant impact on T-cell function. In this study, we explored how these ECM properties-density and fibrillar alignment-affect T-cell behavior using three-dimensional (3D) collagen matrices that mimic these conditions. Our results show that increased matrix stiffness, whether due to higher density or alignment, significantly suppresses T-cell activation, reduces cytokine production, and limits proliferation, largely through enhanced YAP signaling. Individually, matrix alignment appears to lower actin levels in activated T-cells and changes migration behavior in both resting and activated T-cells, an effect not observed in matrices with randomly oriented fibrils. Notably, inhibiting YAP signaling was able to restore T-cell activation and improve immune responses, suggesting a potential strategy to boost the effectiveness of immunotherapy in stiff ECM environments. Overall, this study provides new insights into how ECM characteristics influence T-cell function, offering potential avenues for overcoming ECM-induced immunosuppression in diseases such as cancer.
    Keywords:  3D cell culture; Matrix microarchitecture; Mechanotransduction; T-cell; YAP signaling
    DOI:  https://doi.org/10.1016/j.biomaterials.2024.122900
  4. Proc Natl Acad Sci U S A. 2024 Nov 05. 121(45): e2410806121
    Tuning porosity of macroporous hydrogels enables rapid rates of stress relaxation and promotes cell expansion and migration.
    Bryan A Nerger, Kirti Kashyap, Brendan T Deveney, Junzhe Lou, Blake F Hanan, Qi Liu, Andrew Khalil, Tenzin Lungjangwa, Maria Cheriyan, Anupam Gupta, Rudolf Jaenisch, David A Weitz, L Mahadevan, David J Mooney.
      Extracellular matrix (ECM) viscoelasticity broadly regulates cell behavior. While hydrogels can approximate the viscoelasticity of native ECM, it remains challenging to recapitulate the rapid stress relaxation observed in many tissues without limiting the mechanical stability of the hydrogel. Here, we develop macroporous alginate hydrogels that have an order of magnitude increase in the rate of stress relaxation as compared to bulk hydrogels. The increased rate of stress relaxation occurs across a wide range of polymer molecular weights (MWs), which enables the use of high MW polymer for improved mechanical stability of the hydrogel. The rate of stress relaxation in macroporous hydrogels depends on the volume fraction of pores and the concentration of bovine serum albumin, which is added to the hydrogels to stabilize the macroporous structure during gelation. Relative to cell spheroids encapsulated in bulk hydrogels, spheroids in macroporous hydrogels have a significantly larger area and smaller circularity because of increased cell migration. A computational model provides a framework for the relationship between the macroporous architecture and morphogenesis of encapsulated spheroids that is consistent with experimental observations. Taken together, these findings elucidate the relationship between macroporous hydrogel architecture and stress relaxation and help to inform the design of macroporous hydrogels for materials-based cell therapies.
    Keywords:  biomimetic scaffolds for tissue regeneration; extracellular matrix; poroelasticity; regulation of cell cycle progression; tissue engineering
    DOI:  https://doi.org/10.1073/pnas.2410806121
  5. Adv Healthc Mater. 2024 Oct 29. e2402228
    Cellular Alignment and Matrix Stiffening Induced Changes in Human Induced Pluripotent Stem Cell Derived Cardiomyocytes.
    Andrew House, Anjeli Santillan, Evan Correa, Victoria Youssef, Murat Guvendiren.
      Biological processes are inherently dynamic, necessitating biomaterial platforms capable of spatiotemporal control over cellular organization and matrix stiffness for accurate study of tissue development, wound healing, and disease. However, most in vitro platforms remain static. In this study, a dynamic biomaterial platform comprising a stiffening hydrogel is introduced and achieved through a stepwise approach of addition followed by light-mediated crosslinking, integrated with an elastomeric substrate featuring strain-responsive lamellar surface patterns. Employing this platform, the response of human induced pluripotent stem cell-derived cardiomyocytes (hIPSC-CMs) is investigated to dynamic stiffening from healthy to fibrotic tissue stiffness. The results demonstrate that culturing hIPSC-CMs on physiologically relevant healthy stiffness significantly enhances their function, as evidenced by increased sarcomere fraction, wider sarcomere width, significantly higher connexin-43 content, and elevated cell beating frequency compared to cells cultured on fibrotic matrix. Conversely, dynamic matrix stiffening negatively impacts hIPSC-CM function, with earlier stiffening events exerting a more pronounced hindering effect. These findings provide valuable insights into material-based approaches for addressing existing challenges in hIPSC-CM maturation and have broader implications across various tissue models, including muscle, tendon, nerve, and cornea, where both cellular alignment and matrix stiffening play pivotal roles in tissue development and regeneration.
    Keywords:  cardiac tissue models; fibrosis; hydrogels; methacrylated alginate; photopolymerization; wrinkling patterns
    DOI:  https://doi.org/10.1002/adhm.202402228
  6. Bioact Mater. 2025 Feb;44 152-163
    Ligand presentation controls collective MSC response to matrix stress relaxation in hybrid PEG-HA hydrogels.
    Alexandra N Borelli, Courtney L Schultze, Mark W Young, Bruce E Kirkpatrick, Kristi S Anseth.
      Cell interactions with the extracellular matrix (ECM) influence intracellular signaling pathways related to proliferation, differentiation, and secretion, amongst other functions. Herein, bone-marrow derived mesenchymal stromal cells (MSCs) are encapsulated in a hydrazone crosslinked hyaluronic acid (HA) hydrogel, and the extent of stress relaxation is controlled by systemic introduction of irreversible triazole crosslinks. MSCs form elongated multicellular structures within hydrogels containing RGD peptide and formulated with elastic composition slightly higher than the hydrogel percolation threshold (12 % triazole, 88 % hydrazone). A scaling analysis is presented ( <RgStructure2>12 ∼Nα) to quantify cell-material interactions within these structures with the scaling exponent (α) describing either elongated (0.66) or globular (0.33) structures. Cellular interactions with the material were controlled through peptides to present integrin binding ECM cues (RGD) or cadherin binding cell-cell cues (HAVDI) and MSCs were observed to form highly elongated structures in RGD containing hydrogels ( α=0.56±0.05 ), whereases collapsed structures were observed within HAVDI containing hydrogels ( α=0.39±0.04 ). Finally, cytokine secretion was investigated, and a global increase in secreted cytokines was observed for collapsed structures compared to elongated. Taken together, this study presents a novel method to characterize cellular interactions within a stress relaxing hydrogel where altered cluster morphology imparts changes to cluster secretory profiles.
    Keywords:  Hydrogels; Ligand interactions; Mesenchymal stromal cells; Stress relaxation
    DOI:  https://doi.org/10.1016/j.bioactmat.2024.10.007
  7. Soft Matter. 2024 Oct 30.
    Cell shape and orientation control galvanotactic accuracy.
    Ifunanya Nwogbaga, Brian A Camley.
      Eukaryotic cells sense and follow electric fields during wound healing and embryogenesis - this is called galvanotaxis. Galvanotaxis is believed to be driven by the redistribution of "sensors" - potentially transmembrane proteins or other molecules - through electrophoresis and electroosmosis. Here, we update our previous model of the limits of galvanotaxis due to the stochasticity of sensor movements to account for cell shape and orientation. Computing the Fisher information shows that, in principle, cells have more information about the electric field direction when their long axis is parallel to the field. However, for weak fields, maximum-likelihood estimators may have lower variability when the cell's long axis is perpendicular to the field. In an alternate possibility, we find that if cells instead estimate the field direction by taking the average of all the sensor locations as its directional cue ("vector sum"), this introduces a bias towards the short axis, an effect not present for isotropic cells. We also explore the possibility that cell elongation arises downstream of sensor redistribution. We argue that if sensors migrate to the cell's rear, the cell will tend to expand perpendicular the field - as is more commonly observed - but if sensors migrate to the front, the cell will tend to elongate parallel to the field.
    DOI:  https://doi.org/10.1039/d4sm00952e
  8. Math Biosci Eng. 2024 Aug 01. 21(8): 6731-6757
    Migration and proliferation drive the emergence of patterns in co-cultures of differentiating vascular progenitor cells.
    Jose E Zamora Alvarado, Kara E McCloskey, Ajay Gopinathan.
      Vascular cells self-organize into unique structures guided by cell proliferation, migration, and/or differentiation from neighboring cells, mechanical factors, and/or soluble signals. However, the relative contribution of each of these factors remains unclear. Our objective was to develop a computational model to explore the different factors affecting the emerging micropatterns in 2D. This was accomplished by developing a stochastic on-lattice population-based model starting with vascular progenitor cells with the potential to proliferate, migrate, and/or differentiate into either endothelial cells or smooth muscle cells. The simulation results yielded patterns that were qualitatively and quantitatively consistent with experimental observations. Our results suggested that post-differentiation cell migration and proliferation when balanced could generate between 30-70% of each cell type enabling the formation of vascular patterns. Moreover, the cell-to-cell sensing could enhance the robustness of this patterning. These findings computationally supported that 2D patterning is mechanistically similar to current microfluidic platforms that take advantage of the migration-directed self-assembly of mature endothelial and mural cells to generate perfusable 3D vasculature in permissible hydrogel environments and suggest that stem or progenitor cells may not be fully necessary components in many tissue formations like those formed by vasculogenesis.
    Keywords:   computational model ; endothelial cells ; patterning ; smooth muscle cells ; stem cell differentiation ; vascular development
    DOI:  https://doi.org/10.3934/mbe.2024295
  9. Cell Mol Life Sci. 2024 Oct 26. 81(1): 442
    Stromal softness confines pancreatic cancer growth through lysosomal-cathepsin mediated YAP1 degradation.
    Tianci Zhang, Jingjing Chen, Huan Yang, Xiaoyan Sun, Yiran Ou, Qiang Wang, Mouad Edderkaoui, Sujun Zheng, Feng Ren, Ying Tong, Richard Hu, Jiaye Liu, Yun Gao, Stephen J Pandol, Yuan-Ping Han, Xiaofeng Zheng.
      The progression and malignancy of many tumors are associated with increased tissue stiffness. Conversely, the oncogenically transformed cells can be confined in soft stroma. Yet, the underlying mechanisms by which soft matrix confines tumorigenesis and metastasis remain elusive. Here, we show that pancreatic cancer cells are suppressed in the soft extracellular matrix, which is associated with YAP1 degradation through autophagic-lysosomal pathway rather than Hippo signal mediated proteasome pathway. In the soft stroma, PTEN is upregulated and activated, which consequently promotes lysosomal biogenesis, leading to the activation of cysteine-cathepsins for YAP1 degradation. In vitro, purified cathepsin L can directly digest YAP1 under acidic conditions. Lysosomal stress, either caused by chloroquine or overexpression of cystatin A/B, results in YAP1 accumulation and malignant transformation. Likewise, liver fibrosis induced stiffness can promote malignant potential in mice. Clinical data show that down-regulation of lysosomal biogenesis is associated with pancreatic fibrosis and stiffness, YAP1 accumulation, and poor prognosis in PDAC patients. Together, our findings suggest that soft stroma triggers lysosomal flux-mediated YAP1 degradation and induces cancer cell dormancy.
    Keywords:  Autophagy; Pancreatic ductal adenocarcinoma; Soft matrix; Tumor dormancy; Yes-associated protein 1
    DOI:  https://doi.org/10.1007/s00018-024-05466-y
  10. Front Oncol. 2024 ;14 1470379
    Modeling epithelial-mesenchymal transition in patient-derived breast cancer organoids.
    Neta Bar-Hai, Rakefet Ben-Yishay, Sheli Arbili-Yarhi, Naama Herman, Vered Avidan-Noy, Tehillah Menes, Aiham Mansour, Fahim Awwad, Nora Balint-Lahat, Gil Goldinger, Goni Hout-Siloni, Mohammad Adileh, Raanan Berger, Dana Ishay-Ronen.
      Cellular plasticity is enhanced by dedifferentiation processes such as epithelial-mesenchymal transition (EMT). The dynamic and transient nature of EMT-like processes challenges the investigation of cell plasticity in patient-derived breast cancer models. Here, we utilized patient-derived organoids (PDOs) as a model to study the susceptibility of primary breast cancer cells to EMT. Upon induction with TGF-β, PDOs exhibited EMT-like features, including morphological changes, E-cadherin downregulation and cytoskeletal reorganization, leading to an invasive phenotype. Image analysis and the integration of deep learning algorithms enabled the implantation of microscopy-based quantifications demonstrating repetitive results between organoid lines from different breast cancer patients. Interestingly, epithelial plasticity was also expressed in terms of alterations in luminal and myoepithelial distribution upon TGF-β induction. The effective modeling of dynamic processes such as EMT in organoids and their characteristic spatial diversity highlight their potential to advance research on cancer cell plasticity in cancer patients.
    Keywords:  EMT; breast cancer; cell plasticity; organoids; tumor heterogeneity
    DOI:  https://doi.org/10.3389/fonc.2024.1470379
  11. Proc Natl Acad Sci U S A. 2024 Nov 05. 121(45): e2410654121
    Emergent behaviors of buckling-driven elasto-active structures.
    Yuchen Xi, Tom Marzin, Richard B Huang, Trevor J Jones, P-T Brun.
      Active systems of self-propelled agents, e.g., birds, fish, and bacteria, can organize their collective motion into myriad autonomous behaviors. Ubiquitous in nature and across length scales, such phenomena are also amenable to artificial settings, e.g., where brainless self-propelled robots orchestrate their movements into spatial-temporal patterns via the application of external cues or when confined within flexible boundaries. Like their natural counterparts, these approaches typically require many units to initiate collective motion, so controlling the ensuing dynamics is challenging. Here, we demonstrate a simple mechanism that leverages nonlinear elasticity to tame near-diffusive motile particles in forming structures capable of directed motion and other emergent behaviors. Our elasto-active system comprises two centimeter-sized self-propelled microbots connected with elastic beams. These microbots exert forces that suffice to buckle the beam and set the structure in motion. We first rationalize the physics of the interaction between the beam and the microbots. Then we use reduced-order models to predict the interactions of our elasto-active structures with boundaries, e.g., walls and constrictions, and demonstrate how they can exhibit remarkable emergent behaviors such as maze navigation. These findings demonstrate that allowing and understanding changes in body morphology can enhance the capabilities of active matter systems and enable the design of robotic materials capable of space exploration, adaptation, and complex interactions with their surrounding environment.
    Keywords:  active matter; elasticity; morphological computation; soft matter; soft robotics
    DOI:  https://doi.org/10.1073/pnas.2410654121
  12. Chembiochem. 2024 Oct 27. e202400733
    Supramolecular Conductive Hydrogels for Tissue Engineering Applications.
    Aashwini Bhavsar, Falguni Pati, Priyadarshi Chakraborty.
      Owing to their unique attributes, including reversibility, specificity, directionality, and tunability, supramolecular biomaterials have evolved as an excellent alternative to conventional biomaterials like polymers, ceramics, and metals. Supramolecular hydrogels, in particular, have garnered significant interest because their fibrous architecture, high water content, and interconnected 3D network resemble the extracellular matrix to some extent. Consequently, supramolecular hydrogels have been used to develop biomaterials for tissue engineering. Supramolecular conductive hydrogels combine the advantages of supramolecular soft materials with the electrical properties of metals, making them highly relevant for electrogenic tissue engineering. Given the versatile applications of these hydrogels, it is essential to periodically review high-quality research in this area. In this review, we focus on recent advances in supramolecular conductive hydrogels, particularly their applications in tissue engineering. We discuss the conductive components of these hydrogels and highlight notable reports on their use in cardiac, skin, and neural tissue engineering. Additionally, we outline potential future developments in this field.
    Keywords:  Supramolecular hydrogel; bioelectronics; carbon nanomaterials; conductive polymers; tissue engineering
    DOI:  https://doi.org/10.1002/cbic.202400733
  13. Life Sci. 2024 Oct 27. pii: S0024-3205(24)00768-9. [Epub ahead of print] 123178
    Mechano-assisted strategies to improve cancer chemotherapy.
    Shanshan Zhu, Guorui Jin, Xiaocong He, Yuan Li, Feng Xu, Hui Guo.
      Chemotherapy remains a cornerstone in cancer treatment; however, its effectiveness is frequently undermined by the development of drug resistance. Recent studies underscores the pivotal role of the tumor mechanical microenvironment (TMME) and the emerging field of mechanical nanomedicine in tackling chemo-resistance. This review offers an in-depth analysis of mechano-assisted strategies aimed at mitigating chemo-resistance through the modification of the TMME and the refinement of mechanical nanomedicine delivery systems. We explore the potential of targeting abnormal tumor mechanical properties as a promising avenue for enhancing the efficacy of cancer chemotherapy, which offers novel directions for advancing future cancer therapies, especially from the mechanomedicine perspective.
    Keywords:  Chemo-resistance; Nanomedicine mechanical properties; Tumor mechanical microenvironment
    DOI:  https://doi.org/10.1016/j.lfs.2024.123178
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