bims-ecemfi Biomed News
on ECM and fibroblasts
Issue of 2024–12–29
six papers selected by
Badri Narayanan Narasimhan, University of California, San Diego
  1. Sliding Hydrogels Reveal the Modulation of Mechanosensing Attenuates the Inflammatory Phenotype of Osteoarthritic Chondrocytes in 3D.
  2. Macrophage and osteosarcoma cell crosstalk is dependent on oxygen tension and 3D culture.
  3. Mesenchymal cell contractility regulates villus morphogenesis and intestinal architecture.
  4. Global versus local matrix remodeling drives rotational versus invasive collective migration of epithelial cells.
  5. Engineering the 3D structure of organoids.
  6. Enhanced Maturity and Functionality of Vascular Human Liver Organoids through 3D Bioprinting and Pillar Plate Culture.
  1. J Biomed Mater Res A. 2025 Jan;113(1): e37861
    Sliding Hydrogels Reveal the Modulation of Mechanosensing Attenuates the Inflammatory Phenotype of Osteoarthritic Chondrocytes in 3D.
    Manish Ayushman, Hung-Pang Lee, Pranay Agarwal, Georgios Mikos, Xinming Tong, Sarah Jones, Sauradeep Sinha, Stuart Goodman, Nidhi Bhutani, Fan Yang.
      Osteoarthritis (OA) is a prevalen degenerative joint disease with no FDA-approved therapies that can halt or reverse its progression. Current treatments address symptoms like pain and inflammation, but not underlying disease mechanisms. OA progression is marked by increased inflammation and extracellular matrix (ECM) degradation of the joint cartilage. While the role of biochemical cues has been widely studied for OA, how matrix mechanical cues influence OA phenotype remains poorly understood. Using sliding hydrogels (SGs) as a tool, we examine how local matrix compliance in 3D modulates OA chondrocyte phenotype and associated mechanosensing. We demonstrate that local matrix compliance reduces the inflammatory phenotype of OA chondrocytes, as indicated by decreased gene expression of catabolic markers and proinflammatory cytokine secretion. This is achieved via significantly reduced nuclear NF-κB expression and signaling in OA chondrocytes. Live cell imaging shows enhanced cellular and nuclear dynamics with increased matrix deformation in the compliant SG. Blocking cellular dynamics negates SG compliance-induced benefits in reducing OA inflammatory phenotype. Further, SG alters nuclear mechanosensing in OA as indicated by increased nuclear lamin reinforcement and chromatin condensation. Finally, we demonstrate that a drug inhibiting histone lysine demethylase to modulate chromatin accessibility reduces OA inflammation in 3D hydrogels. These findings advance our understanding of how ECM mechanics regulate OA mechanobiology and progression and highlight potential disease-modifying treatments via epigenetic and mechanosensing-based therapies.
    Keywords:  chromatin accessibility; hydrogels; inflammation; matrix mechanics; mechanosensing; osteoarthritis; three‐dimensional
    DOI:  https://doi.org/10.1002/jbm.a.37861
  2. Biomater Adv. 2024 Dec 16. pii: S2772-9508(24)00397-2. [Epub ahead of print]169 214154
    Macrophage and osteosarcoma cell crosstalk is dependent on oxygen tension and 3D culture.
    Katherine H Griffin, Isabel S Sagheb, Thomas P Coonan, Fernando A Fierro, R Lor Randall, J Kent Leach.
      Osteosarcoma (OS), the most common form of primary bone cancer in young adults, has had no improvements in clinical outcomes in 50 years. This highlights a critical need to advance mechanistic understanding of OS to further therapeutic discovery, which will only be possible with accurate models of the disease. Compared to traditional monolayer studies and preclinical models, in vitro models that better replicate the three-dimensional (3D) bone marrow microenvironment will facilitate methodical investigations of the events and factors that drive OS progression. Herein, we use fibrin-alginate interpenetrating network (FA IPN) hydrogels to model the hematological bone marrow environment. We interrogated the effects of oxygen tension, 3D culture, and macrophage phenotype on OS behavior and specifically examine the immunomodulatory crosstalk between OS and macrophages. We observe that OS is more sensitive to oxygen tension when cultured in 3D. Specifically, both highly and less metastatic OS exhibit decreased changes in DNA content over time in 3D, but then demonstrate diverging behaviors in heterotypic culture with macrophages. OS response to macrophages differs as a function of metastatic potential, where highly metastatic OS shows increased immunosuppression that varies with oxygen tension but relies on direct coculture conditions. To our knowledge, this is among the first work to report the effects of 3D culture on the interplay between OS and macrophages in a coculture microenvironment. Together, these data introduce FA IPNs as a promising platform for cancer research and emphasize the importance of novel models for the mechanistic study of OS.
    Keywords:  Alginate; Coculture; Hydrogel; Hypoxia; Immunomodulation
    DOI:  https://doi.org/10.1016/j.bioadv.2024.214154
  3. Dev Biol. 2024 Dec 19. pii: S0012-1606(24)00284-7. [Epub ahead of print]519 96-105
    Mesenchymal cell contractility regulates villus morphogenesis and intestinal architecture.
    Taylor D Hinnant, Caroline Joo, Terry Lechler.
      The large absorptive surface area of the small intestine is imparted by finger-like projections called villi. Villi formation is instructed by stromal-derived clusters of cells which have been proposed to induce epithelial bending through actomyosin contraction. Their functions in the elongation of villi have not been studied. Here, we explored the function of mesenchymal contractility at later stages of villus morphogenesis. We induced contractility specifically in the mesenchyme of the developing intestine through inducible overexpression of the RhoA GTPase activator Arhgef11. This resulted in overgrowth of the clusters through a YAP-mediated increase in cell proliferation. While epithelial bending occurred in the presence of contractile clusters, the resulting villi had architectural defects, being shorter and wider than controls. These villi also had defects in epithelial organization and the establishment of nutrient-absorbing enterocytes. While ectopic activation of YAP resulted in similar cluster overgrowth and wider villi, it did not affect villus elongation or enterocyte differentiation, demonstrating roles for contractility in addition to proliferation. We find that the specific contractility-induced effects were dependent upon cluster interaction with the extracellular matrix. Together, these data demonstrate effects of contractility on villus morphogenesis and distinguish separable roles for proliferation and contractility in controlling intestinal architecture.
    Keywords:  Actomyosin contractility; Mesenchyme cluster; Morphogenesis; Small intestine; Villus development; YAP
    DOI:  https://doi.org/10.1016/j.ydbio.2024.12.012
  4. Dev Cell. 2024 Dec 17. pii: S1534-5807(24)00721-4. [Epub ahead of print]
    Global versus local matrix remodeling drives rotational versus invasive collective migration of epithelial cells.
    Sural K Ranamukhaarachchi, Alyssa Walker, Man-Ho Tang, William D Leineweber, Sophia Lam, Wouter-Jan Rappel, Stephanie I Fraley.
      The coordinated movement of cell collectives is essential for normal epithelial tissue development, maintenance, and cancer progression. Here, we report on a minimal 3D extracellular matrix (ECM) system wherein both invasive collective migration (ICM) and rotational collective migration (RCM) arise spontaneously from individually seeded epithelial cells of mammary and hepatic origin, regardless of whether they express adherens junctions, and lead to ductal-like and acinar-like structures, respectively. Quantitative microscopy and cellular Potts modeling reveal that initial differences in cell protrusion dynamics and matrix-remodeling localization generate RCM and ICM behavior in confining 3D ECM. Matrix-remodeling activity by matrix metalloproteinases (MMPs) is localized to the base of protrusions in cells that initiate ICM, whereas RCM does not require MMPs and is associated with ITGβ1-mediated remodeling localized globally around the cell body. Further analysis in vitro and in vivo supports the concept that distinct matrix-remodeling strategies encode collective migration behaviors and tissue structure.
    Keywords:  ITGβ1; MT1-MMP; adherens junctions; adhesion; collective migration; invasive migration; matrix metalloproteinase; matrix remodeling; rotational migration
    DOI:  https://doi.org/10.1016/j.devcel.2024.11.021
  5. Stem Cell Reports. 2024 Dec 10. pii: S2213-6711(24)00323-0. [Epub ahead of print] 102379
    Engineering the 3D structure of organoids.
    Samuel P Moss, Ezgi Bakirci, Adam W Feinberg.
      Organoids form through the sel f-organizing capabilities of stem cells to produce a variety of differentiated cell and tissue types. Most organoid models, however, are limited in terms of the structure and function of the tissues that form, in part because it is difficult to regulate the cell type, arrangement, and cell-cell/cell-matrix interactions within these systems. In this article, we will discuss the engineering approaches to generate more complex organoids with improved function and translational relevance, as well as their advantages and disadvantages. Additionally, we will explore how biofabrication strategies can manipulate the cell composition, 3D organization, and scale-up of organoids, thus improving their utility for disease modeling, drug screening, and regenerative medicine applications.
    Keywords:  3D bioprinting; biofabrication; organoids; spheroids; stem cells; vascularization
    DOI:  https://doi.org/10.1016/j.stemcr.2024.11.009
  6. ACS Biomater Sci Eng. 2024 Dec 27.
    Enhanced Maturity and Functionality of Vascular Human Liver Organoids through 3D Bioprinting and Pillar Plate Culture.
    Vinod Kumar Reddy Lekkala, Sunil Shrestha, Ayah Al Qaryoute, Sanchi Dhinoja, Prabha Acharya, Abida Raheem, Pudur Jagadeeswaran, Moo-Yeal Lee.
      Liver tissues, composed of hepatocytes, cholangiocytes, stellate cells, Kupffer cells, and sinusoidal endothelial cells, are differentiated from endodermal and mesodermal germ layers. By mimicking the developmental process of the liver, various differentiation protocols have been published to generate human liver organoids (HLOs) in vitro using induced pluripotent stem cells (iPSCs). However, HLOs derived solely from the endodermal germ layer often encounter technical hurdles such as insufficient maturity and functionality, limiting their utility for disease modeling and hepatotoxicity assays. To overcome this, we separately differentiated EpCAM+ endodermal progenitor cells (EPCs) and mesoderm-derived vascular progenitor cells (VPCs) from the same human iPSC line. These cells were then mixed in a BME-2 matrix and concurrently differentiated into vascular human liver organoids (vHLOs). Remarkably, vHLOs exhibited a significantly higher maturity than vasculature-free HLOs, as demonstrated by increased coagulation factor secretion, albumin secretion, drug-metabolizing enzyme expression, and bile acid transportation. To enhance assay throughput and miniaturize vHLO culture, we 3D bioprinted expandable HLOs (eHLOs) in a BME-2 matrix on a pillar plate platform derived from EPCs and VPCs and compared them with HLOs derived from endoderm alone. Compared to HLOs cultured in a 50 μL BME-2 matrix dome in a 24-well plate, vHLOs cultured on the pillar plate exhibited superior maturity, likely due to enhanced nutrient and signaling molecule diffusion. The integration of physiologically relevant patterned liver organoids with the unique pillar plate platform enhanced the capabilities for high-throughput screening and disease modeling.
    Keywords:  coagulation factor secretion; deep well plate; enhanced organoid maturity; pillar plate; vascular human liver organoids
    DOI:  https://doi.org/10.1021/acsbiomaterials.4c01658
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