bims-ecemfi Biomed News
on ECM and fibroblasts
Issue of 2026–07–12
seven papers selected by
Badri Narayanan Narasimhan, University of California, San Diego
  1. Nascent extracellular matrix: the missing piece in hydrogel design.
  2. Elastic scaffolds reinforced stem cell-laden collagen-derived hybrid hydrogels to engineer 3D anisotropic cellular microenvironment.
  3. Distinct motility and pro-fibrotic effect of renal tubule-derived extracellular vesicles in fibrotic extracellular matrix.
  4. Self-generated hydrogel ejects bacterial cells for localized biofilm dispersion.
  5. Antioxidant Ascorbic Acid Influences Cell-mediated Alterations in Localized Hydrogel Crosslinking and Affects Neo-Cartilage Connectivity in Hydrolytically Degradable Hydrogels.
  6. Calcium ions released from alginate hydrogel promote wound healing by enhancing fibroblast activity.
  7. Spatially Organized Human Ovarian Spheroids Instruct Endometrial Morphogenesis.
  1. Cell Biomater. 2026 Jun 16. pii: 100404. [Epub ahead of print]2(6):
    Nascent extracellular matrix: the missing piece in hydrogel design.
    Joshua Yu-Chung Liu, Matthew L Tan, Claudia Loebel.
      Almost every cell in vivo is surrounded by the extracellular matrix (ECM), which contributes to cell and tissue fate. Biomaterials, especially engineered hydrogels, have emerged as platforms to recreate the biochemical and mechanical properties of ECM. Yet most approaches still assume that cells directly respond to the engineered hydrogel, although there is increasing evidence that numerous cell types rapidly deposit newly synthesized (nascent) ECM (nECM). Studies have now shown that this nECM accumulates at the cell-hydrogel interface, where it also contributes to a cell's fate. In this perspective, we first highlight key studies describing the nECM as a regulator of cell fate. Next, we provide guidelines based on physicochemical principles for studying nECM through spatiotemporal mapping, mechanical/structural measurements, biochemical characterization, and functional assays. Finally, building upon existing hydrogel engineering tools, we propose chemical- and protein-engineering approaches to specifically engineer the nECM to more precisely control cell-matrix interactions.
    Keywords:  Extracellular matrix; cell culture; cell-matrix interactions; hydrogel; protein engineering
    DOI:  https://doi.org/10.1016/j.celbio.2026.100404
  2. Mater Today Bio. 2026 Aug;39 103385
    Elastic scaffolds reinforced stem cell-laden collagen-derived hybrid hydrogels to engineer 3D anisotropic cellular microenvironment.
    Hongjuan Weng, Lei He, Wen Chen, Vahid Ansari, Sabine van Rijt, Monize C Decarli, Katrien V Bernaerts, Lorenzo Moroni.
      Replicating complex, robust and organized three-dimensional (3D) cellular microenvironments that exist in many human tissues is essential for understanding the cell-matrix interactions and paving the foundation for tissue engineering. However, biofabrication strategies for in vitro modeling such complex, mechanically robust, and 3D anisotropic cell networks by cell-laden hydrogel-scaffolds are far less developed. This work describes 3D anisotropic soft-hard hybrid scaffolds with either single macroscale anisotropy or dual macro-micro-scale anisotropy by incorporating collagen-derived hydrogels with human mesenchymal stem cells (hMSCs) and 3D printed poly(ester amide) (PEA) scaffolds with uniaxial architecture. As a hard scaffold, the uniaxial PEA scaffold endows hybrid constructs with macroscale anisotropy, good elasticity, and mechanical properties. As a soft matrix, methacrylated collagen peptide (COPMA) hydrogel endows hybrid constructs with rapid light response, leading to in situ formation of 3D cellular networks. Magnetic nanoparticles (MNPs) laden COPMA hydrogel endows hybrid constructs with rapid dual light-magnetic response and magnetic-driven dual macro-micro-scale anisotropy. PEA-COPMA constructs act as biocompatible biochemical cues to induce the encapsulated hMSCs to attach and spread between the scaffold and the hydrogel. These encapsulated hMSCs showed improved cell spreading, alignment and differentiation in the dual macro-micro-scaled aligned PEA-COPMA-MNP constructs due to the combination of biochemical and biophysical anisotropic cues. This hybrid manufacturing strategy, which directly incorporates light-magnetic-responsive cell-laden nanocomposite hydrogels with elastic organized scaffolds, shows great potential in developing advanced mechanically reinforced 3D organized in vitro cellular microenvironments.
    Keywords:  Biochemical cues; Biophysical anisotropic cue; Cell alignment; Nanocomposite collagen-derived hydrogels; Soft-hard hybrid scaffold; poly(ester amide) scaffolds
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103385
  3. Acta Biomater. 2026 Jul 07. pii: S1742-7061(26)00444-7. [Epub ahead of print]
    Distinct motility and pro-fibrotic effect of renal tubule-derived extracellular vesicles in fibrotic extracellular matrix.
    An-Ran Shen, Tian Gao, Yu-Qi Fu, Hao-Qi Zhu, Yan Bao, Ning Li, Tao-Tao Tang, Yi Cao, Bi-Cheng Liu, Bin Xue, Lin-Li Lv.
      Extracellular vesicles (EVs) facilitate intercellular communication by traversing the extracellular matrix (ECM). However, their motility within fibrotic ECM and its role in fibrosis development remain unclear. We engineered stress-relaxing (SR) hydrogels of tunable stiffness (2, 50 kPa) through dynamic crosslinking of short peptide (WGG(KA)) and heparin to mimic normal and fibrotic ECM. Super-resolution nanoimaging and quantitative three dimensional (3D) single-particle tracking (SPT) of single EV were performed, and the motion dynamics was quantified. The interplay between EVs and ECM was further investigated, particularly its effects on fibroblast activation and renal fibrosis. It was identified that both normal and fibrotic kidney-derived EVs exhibited confined Brownian-like motion according to 3D SPT, with enhanced mobility in the stiffer (50 kPa) hydrogel. Notably, fibrotic tubule-derived EVs carried higher levels of integrin β6 (ITGB6), which reduced their mobility within the hydrogel-based ECM mimic, as confirmed by the restoration of motility upon ITGB6 blocking or digestion. This suggested that EV motility may be influenced by the interplay between ECM stiffness and the intrinsic properties of the EVs. Furthermore, enrichment of ITGB6 on fibrotic tubule-derived EVs promotes local retention, thereby increasing EV-fibroblast interaction and profibrotic signaling. This indicated the underappreciated role of EV in fibrosis related to its motility and its interplay with fibroblast in fibrotic niche. Our study provides new insights into the mechano-dependent mechanisms governing EV motility within the fibrotic ECM. STATEMENT OF SIGNIFICANCE: Extracellular vesicles (EVs) play key roles in cell communication, but how they move through fibrotic tissue remains poorly understood. This study reveals that kidney-derived EVs exhibit confined Brownian-like motion within engineered hydrogels mimicking fibrotic extracellular matrix. We found that EVs from fibrotic tubules carry elevated integrin β6, which restricts their mobility and promotes pro-fibrotic signaling by increasing EV-fibroblast interaction. Our study provides new insights into the mechano-dependent mechanisms governing EV motility within the fibrotic ECM. This work provide a biophysical perspective for understanding EVs mediated pathological communication in fibrosis.
    Keywords:  Extracellular matrix; Extracellular vesicles; Fibrosis; Integrin β6; Stress-relaxing hydrogel
    DOI:  https://doi.org/10.1016/j.actbio.2026.07.007
  4. Nat Microbiol. 2026 Jul 07.
    Self-generated hydrogel ejects bacterial cells for localized biofilm dispersion.
    Todd Kwang-Tao Chou, Alejandra Dau-Martinez, Júlia Vicens-Figueres, Arvind Gouttumukkala, Leticia Galera-Laporta, Jordi Garcia-Ojalvo, Gürol M Süel.
      Bacteria residing in biofilms are embedded in an extracellular matrix. Whereas biofilm formation is well studied, less is known about biofilm dispersion, although enzymatic extracellular matrix degradation is suspected to play a key role. Here we show that Bacillus subtilis biofilms can alternatively eject a specific cell type, locally and anisotropically, using mechanical forces arising from a self-generated hydrogel. Single-cell resolution imaging combined with mathematical modelling, and chemical and genetic perturbations, show that the production of the extracellular poly-γ-glutamic acid (γ-PGA) polymer is necessary to drive this cell ejection. Specifically, osmotic pressure from the γ-PGA hydrogel propels interior cells through the outer layers to break free from the biofilm. We demonstrate control over this process through γ-PGA modulation such that biofilm dispersion can be either inhibited or promoted. Forceful ejection driven by γ-PGA has so far only been described in marine organisms such as jellyfish. Our discovery of biofilm cell ejection via γ-PGA thus reveals not only a previously uncharacterized biofilm dispersion mechanism but also an unexpected mechanistic parallel to evolutionarily distant Cnidaria.
    DOI:  https://doi.org/10.1038/s41564-026-02413-4
  5. Macromol Biosci. 2026 Jul;26(7): e00481
    Antioxidant Ascorbic Acid Influences Cell-mediated Alterations in Localized Hydrogel Crosslinking and Affects Neo-Cartilage Connectivity in Hydrolytically Degradable Hydrogels.
    Mollie M Maples, Chun-Yi Chang, Nicole B Day, Stephanie J Bryant.
      Photopolymerizable and degradable poly(ethylene glycol) (PEG) hydrogels are a promising platform to deliver chondrocytes for cartilage tissue engineering. Previous studies reported that cells are exposed to and react with free-radicals produced during encapsulation, creating a pericellular region of reduced crosslink density measured by the distance Rd. This study tests the hypothesis that increasing Rd improves spatial elaboration of deposited extracellular matrix (ECM) (i.e., micro-tissue) in a degrading hydrogel. Chondrocytes pre-treated or not with the antioxidant ascorbic acid atlow (1 nM) and high (1000 nM) concentrations prior to encapsulation resulted in increasingly larger Rd's: 3.3 (0 nM), 6.7 (1 nM), and 10 (1000 nM) µm. Encapsulated chondrocytes when cultured up to ten weeks, produced micro-tissues within the hydrogels. The median micro-tissue area increased by 29% (1 nM) and 570% (1000 nM) compared to 0 nM condition. This work shows that bolstering antioxidant defense mechanisms enhances chondrocyte inhibition of the polymerization immediately around the cell, resulting in larger regions of reduced crosslinking. This local variation in network structure, which degrades more quickly, led to improved neotissue assembly and larger micro-tissues, comprised primarily of sulfated glycosaminoglycans and collagen type II. This approach offers a novel way to improve ECM elaboration and interconnectivity in free-radical polymerized hydrogels for tissue engineering.
    Keywords:  antioxidant; chondrocyte; extracellular matrix; free‐radical polymerization; hydrogel
    DOI:  https://doi.org/10.1002/mabi.202300481
  6. Front Bioeng Biotechnol. 2026 ;14 1828848
    Calcium ions released from alginate hydrogel promote wound healing by enhancing fibroblast activity.
    Lei Zhang, Ying Luo, Shubo Liu, Huiting Deng, Yingtang Gao.
      Hydrogels are widely used as wound dressings owing to their biocompatibility, high water content, and ability to mimic extracellular matrix functions. Alginate (ALG) is a natural polysaccharide that forms ionically crosslinked hydrogels in the presence of calcium, where Ca2+ not only stabilizes the crosslinked network but also regulates cell behavior, which is essential for wound repair. In this study, ALG hydrogels were prepared with CaCl2 at 20, 50, 100, and 200 mM, and their gelation, rheological properties, calcium ion release, and cellular responses were systematically evaluated. The 100 mM CaCl2 formulation exhibited the optimal mechanical stability and bioactivity, markedly promoting fibroblast proliferation, migration, and extracellular matrix organization in vitro. Application of this hydrogel to a rat model with full-thickness skin defects significantly accelerated wound closure and tissue regeneration. Transcriptomic analysis further confirmed activation of the calcium signaling pathway in fibroblasts. These findings highlight the pivotal role of Ca2+ in orchestrating fibroblast activity, providing an optimized alginate-based dressing for effective wound healing.
    Keywords:  alginate hydrogel; calcium crosslinking; diabetic wound; fibroblast activation; wound healing
    DOI:  https://doi.org/10.3389/fbioe.2026.1828848
  7. Adv Sci (Weinh). 2026 Jul 09. e76538
    Spatially Organized Human Ovarian Spheroids Instruct Endometrial Morphogenesis.
    Maria João Sousa, Silke De Vriendt, Lixian Liu, Thalles Fernando Rocha Ruiz, Hugo Vankelecom, Christiani Andrade Amorim.
      The human ovarian-endometrial axis operates through coordinated, dynamic endocrine signaling that cannot be faithfully reproduced by static hormone supplementation. While endometrial organoids (EMOs) respond to exogenous estradiol and progesterone, whether a spatially organized human ovarian endocrine unit can instruct epithelial morphogenesis through physiologically integrated signaling remains unknown. Here, we engineered a multilayered human follicle-like spheroid composed of primary granulosa cells and stromal-derived theca-like cells (SPHEGaT), recreating architectural and steroidogenic features of the ovarian follicle. These constructs generated sustained biologically active concentrations of estradiol and progesterone while maintaining high viability and low hypoxic burden. When co-cultured with EMOs, SPHEGaTs induced progressive epithelial remodeling characterized by folding morphogenesis, increased progesterone receptor expression, and upregulation of secretory/progesterone-responsive genes including PAEP, SPP1 and HSD17B2. Strikingly, partial steroid depletion did not abolish organoid folding, whereas static supplementation with exogenous estradiol and progesterone failed to restore the differentiation phenotype. These findings suggest that endometrial remodeling is influenced not merely by hormone concentration, but also by additional signaling cues present within the SPHEGaT-derived microenvironment. Together, this work establishes a human 3D platform in which integrated ovarian-derived signaling supports epithelial morphogenesis, providing new framework for studying ovarian-endometrial communication and highlighting the limitations of hormone-only models in reproductive bioengineering.
    Keywords:  Ovarian‐endometrial axis; endometrium organoids; follicle‐like spheroids; reproductive bioengineering; steroidogenesis
    DOI:  https://doi.org/10.1002/advs.76538
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