bims-ecemfi Biomed News
on ECM and fibroblasts
Issue of 2025–09–28
eight papers selected by
Badri Narayanan Narasimhan, University of California, San Diego
  1. Mechanical cues guide the formation and patterning of 3D spheroids in fibrous environments.
  2. Photothermally Powered 3D Microgels Mechanically Regulate Mesenchymal Stem Cells Under Anisotropic Force.
  3. Collagen Scaffold Viscoelasticity Regulates Muscle Cell Phenotype.
  4. Extracellular matrix architecture promotes immunosuppressive microenvironments in pancreatic cancer.
  5. SCHEPHERD: A universal platform for high-throughput, high-resolution, and programmable control of cell behavior through bioelectric stimulation.
  6. Tissue-like Fracture Toughness and Stress-Relaxation Ability in PVA-Agar-Based Hydrogels for Biomedical Applications.
  7. AggreBots: Configuring CiliaBots through guided, modular tissue aggregation.
  8. Epigenomic Heterogeneity of Non-Functional Pancreatic Neuroendocrine Tumors Uncovered by Single nucleus and Spatial ATAC Profiling.
  1. PNAS Nexus. 2025 Sep;4(9): pgaf263
    Mechanical cues guide the formation and patterning of 3D spheroids in fibrous environments.
    Sharan Sharma, Atharva Agashe, Jennifer C Hill, Keya Ganguly, Puja Sharma, Tara D Richards, Weijian Huang, David J Kaczorowski, Pablo G Sanchez, Rakesh Kapania, Julie A Phillippi, Amrinder S Nain.
      Multicellular spheroids have shown great promise in 3D biology. Many techniques exist to form spheroids, but how cells take mechanical advantage of native fibrous extracellular matrix (ECM) to form spheroids remains unknown. Here, we identify the role of fiber diameter, architecture, and cell contractility on spheroids' spontaneous formation and growth in ECM-mimicking fiber networks. We show that matrix deformability revealed through force measurements on aligned fiber networks promotes spheroid formation independent of fiber diameter. At the same time, larger-diameter crosshatched networks of low deformability abrogate spheroid formation. Thus, designing fiber networks of varying diameters and architectures allows spatial patterning of spheroids and monolayers simultaneously. Forces quantified during spheroid formation revealed the contractile role of Rho-associated protein kinase in spheroid formation and maintenance. Interestingly, we observed spheroid-spheroid and multiple spheroid mergers initiated by cell exchanges to form cellular bridges connecting the two spheroids. Unexpectedly, we found large pericyte spheroids contract rhythmically. Transcriptomic analysis revealed striking changes in cell-cell, cell-matrix, and mechanosensing gene expression profiles concordant with spheroid assembly on fiber networks. Overall, we ascertained that contractility and network deformability work together to spontaneously form and pattern 3D spheroids, potentially connecting in vivo matrix biology with developmental, disease, and regenerative biology.
    Keywords:  ECM nanofibers; cell forces; morphogenesis; pericytes; spheroids
    DOI:  https://doi.org/10.1093/pnasnexus/pgaf263
  2. Adv Mater. 2025 Sep 24. e06769
    Photothermally Powered 3D Microgels Mechanically Regulate Mesenchymal Stem Cells Under Anisotropic Force.
    Chen Wang, Nergishan İyisan, Philipp Harder, Valentin H K Fell, Viktorija Kozina, Hendrik Dietz, Olivia M Merkel, Berna Özkale.
      Exogenous forces significantly influence mammalian cell behavior, yet current strategies fail to resolve signaling processes between individual cells under conditions that accurately mimic the native microenvironment. This work presents a new cell culture technology capable of applying spatially patterned exogenous forces on individual cells within multicellular clusters encased in three-dimensional (3D) hydrogel matrices. Photothermally powered 3D microgels containing stem cells and integrated force generators are engineered to investigate intercellular communication under anisotropic forces with excellent spatial resolution (≈1 µm). Varying force patterns, such as uniform compression versus spatially heterogeneous tension, are achieved in 3D by relying on the synergistic effect of plasmonic gold nanorods and thermally responsive co-polymers under light actuation. The microgels generate 17-34 nN force locally, which activates mechanically sensitive ion channels in encapsulated cells stimulated with isotropically applied compression and spatially heterogeneous tension in 3D in a selective manner. Spatially patterned exogenous forces trigger F-actin remodeling, nuclear translocation of Yes-associated protein (YAP) and Runt-related transcription factor 2 (RUNX2) in encapsulated cells following cyclic stimulation. Sustained application of exogenous forces over three days is sufficient to regulate stem cell fate toward osteogenesis. This technology allows combinatorial studies of biomolecular and biophysical cues in 3D, making it suitable for applications in mechanobiology and bioengineering.
    Keywords:  differentiation; mechanical stimulation; mechanotransduction; nanorobotic microgels; photothermal actuation; spatially patterned forces; stem cells
    DOI:  https://doi.org/10.1002/adma.202506769
  3. Adv Healthc Mater. 2025 Sep 23. e02775
    Collagen Scaffold Viscoelasticity Regulates Muscle Cell Phenotype.
    Emily B Roloson, Wei-Hung Jung, Stephanie L McNamara, Catherine L Van Stone, Nuria Lafuente-Gómez, Duncan M Morgan, Georg N Duda, David J Mooney.
      Current biomaterial strategies are typically unable to return skeletal muscle to pre-injury function following damage, resulting in permanent loss of muscle function. Recently, there has been a growing appreciation for the role of matrix viscoelasticity in regenerative processes, and here we address the hypothesis that changes in matrix viscoelasticity regulate muscle cell function. Using norbornene-modified type I collagen hydrogels with a tetrazine-based crosslinker, it is found that myoblast spreading, proliferation, and differentiation are improved on and within slow-relaxing hydrogels. However, satellite cell stemness is maintained only with soft, fast-relaxing hydrogels. This indicates that there is a direct link between the viscoelasticity of collagen-based substrates and muscle cell phenotype in vitro. Together, these studies further the understanding of the role of tissue mechanical properties in directing muscle cell function and provide a tool for guiding specific behaviors necessary for muscle regeneration.
    Keywords:  collagen; myoblast; satellite cell; skeletal muscle; viscoelasticity
    DOI:  https://doi.org/10.1002/adhm.202502775
  4. Matrix Biol. 2025 Sep 18. pii: S0945-053X(25)00084-8. [Epub ahead of print]
    Extracellular matrix architecture promotes immunosuppressive microenvironments in pancreatic cancer.
    Mackenzie K Callaway, Brock J Noonan, Kaylee L Schwertfeger, Paolo P Provenzano.
      Pancreatic ductal adenocarcinoma (PDA) is an aggressive cancer with poor clinical outcomes, due in part to altered fibrotic environments and striking immune dysfunction. Physical properties within tumors, such as aligned extracellular matrix (ECM) fiber architectures, are fundamental to cancer progression and outcome. However, the influence of ECM alignment on immune cell localization and function within tumors, particularly PDA, remains largely unexplored. Here, analysis of mouse and human PDA reveal an inextricable link between collagen architecture and the distribution of immunosuppressive macrophages in both early preinvasive disease and invasive carcinomas. In vitro characterization of primary macrophages demonstrates alignment alone is sufficient to induce elongation, polarization, and immunosuppressive activity, including suppression of CD8+ T cell proliferation and motility. Analysis reveals differential focal adhesion kinase (FAK) activity in aligned macrophages, while FAK inhibition (FAKi) disrupts the immunosuppressive phenotype that emerges from encountering ECM alignment. Furthermore, FAKi in vivo significantly reduces the correlation between elongated immunosuppressive macrophages and aligned collagen, further highlighting the opportunity for FAKi to target stromal immunity. Importantly, the correlation between aligned collagen and immunosuppressive macrophages is also observed in human chronic pancreatitis, a known PDA risk factor that has recently been shown to prime stromal ECM alignments for early dissemination, suggesting that precursor disease is also likely to create stromal memory conducive to early immunosuppression. Taken together, these results support a model in which collagen architecture supports early establishment and maintenance of an immunosuppressive microenvironments and defines a role for targeting stromal matrices to "reprogram" patient immunity.
    Keywords:  Macrophage polarization; contact guidance; immunosuppression; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.matbio.2025.09.004
  5. bioRxiv. 2025 Sep 16. pii: 2025.09.16.674226. [Epub ahead of print]
    SCHEPHERD: A universal platform for high-throughput, high-resolution, and programmable control of cell behavior through bioelectric stimulation.
    Yubin Lin, Jeremy S Yodh, Celeste Rodriguez, Paul Kreymborg, Daniel J Cohen.
      Spanning frogs, fish, and humans, direct-current (DC) bioelectric cues play critical roles beyond neuro-muscular function, such as modulating morphogenesis, immune response, and healing through electrotaxis-electrically directed cell migration. Harnessing this potential requires new tools. However, standardized, accessible, and reproducible infrastructure capable of DC stimulation remains a challenge. We present SCHEPHERD: a universal, electrobioreactor integrating 8 stimulation channels and modular inserts to enable most electrotaxis assays in one device (cells, monolayers, and 3D spheroids), while enabling powerful, new capabilities. SCHEPHERD revealed through parameter sweeps that DC fields act like a 'steering wheel and gas pedal' for cell migration. We then used live confocal imaging to observe electrically reprogrammed F-actin dynamics. Finally, our multi-polar inserts generated complex spatial electrical patterns that reorganize engineered tissue dynamics. By significantly improving accessibility through modularity and an open-source, graphically programmed stimulator, we hope SCHEPHERD can help broaden the community studying these important DC bioelectric phenomena.
    DOI:  https://doi.org/10.1101/2025.09.16.674226
  6. Gels. 2025 Sep 17. pii: 747. [Epub ahead of print]11(9):
    Tissue-like Fracture Toughness and Stress-Relaxation Ability in PVA-Agar-Based Hydrogels for Biomedical Applications.
    Ismael Lamas, Bhuvana L Chandrashekar, Claudia C Biguetti, Mohammad R Islam.
      Soft tissues exhibit remarkable stretchability, fracture toughness, and stress-relaxation ability. They possess a large water content to support cellular processes. Mimicking such a combination of mechanical and physical properties in hydrogels is important for tissue engineering applications but remains challenging. This work aims to develop a hydrogel that can combine excellent mechanical properties with cellular viability. The research focused on polyvinyl alcohol (PVA)/agar double-network (DN) hydrogels, fabricated by thermal gelation and freeze-thawing methods. Their mechanical properties were characterized through tension, compression, fracture, and stress-relaxation tests, and their cellular viability was measured through cytotoxicity tests. The results show that the PVA/agar DN gels are highly stretchable (>200%) and compressible (>30%) while containing high water content. The incorporation of agar by 6 wt% improved the fracture toughness of hydrogels from 1 to 1.76 kJ/m2. The degree of stress-relaxation, a key indicator of gel viscoelastic properties, improved by roughly 170% with an increase in agar content from 0 to 6 wt%. Cytotoxicity analysis showed that the gels, being physically cross-linked, were able to promote cellular proliferation. This work shows that tough and viscoelastic PVA/agar DN gels are suitable for soft tissue engineering applications, especially cartilage repair.
    Keywords:  PVA-agar; double network; fracture toughness; hydrogel; stress–relaxation; viscoelasticity
    DOI:  https://doi.org/10.3390/gels11090747
  7. Sci Adv. 2025 Sep 26. 11(39): eadx4176
    AggreBots: Configuring CiliaBots through guided, modular tissue aggregation.
    Dhruv Bhattaram, Kian Golestan, Xuanshuo Zhang, Shihong Yang, Zhuowei Gong, Steven L Brody, Amjad Horani, Victoria A Webster-Wood, Amir Barati Farimani, Xi Ren.
      Ciliated biobots (CiliaBots) are engineered tissues capable of self-actuated propulsion via exterior motile cilia. While correlations have been observed between CiliaBot motility and morphology, direct control of morphological features to deliver desired motility outcomes remains unexplored. Here, we describe the engineering of aggregated CiliaBots (AggreBots) to augment control over CiliaBot structural parameters and, consequently, motility patterns through guided, modular aggregation of human airway epithelial spheroids [referred to as CiliaBot building blocks (CBBs)]. Multi-CBB aggregation generated rod-, triangle-, and diamond-shaped AggreBots, altering tissue geometry without sacrificing surface cilia density or inter-CBB boundary fidelity. The further introduction of CCDC39-mutated CBBs as cilia-inactive modules enabled the generation of hybrid AggreBots with precision modulation of active cilia distribution, further empowering alterations to motility patterns. Our results demonstrate the potential of AggreBots as living tissue propellers with morphological "levers" by which modifications to tissue motility can be theoretically planned and experimentally verified.
    DOI:  https://doi.org/10.1126/sciadv.adx4176
  8. bioRxiv. 2025 Sep 16. pii: 2025.09.11.675640. [Epub ahead of print]
    Epigenomic Heterogeneity of Non-Functional Pancreatic Neuroendocrine Tumors Uncovered by Single nucleus and Spatial ATAC Profiling.
    Dejiang Wang, Xiangjun Di, Fu Gao, Gaocai Li, Liyun Lin, Shujie He, Di Zhang, Junyi Yu Jin, Yuanxin Liang, Michael Cecchini, Jill Lacy, John Kunstman, Pamela Kunz, Jing Du, Yang Liu.
      Non-functional pancreatic neuroendocrine tumors (NF-PanNETs) account for the majority of neuroendocrine neoplasms arising in the pancreas and exhibit substantial clinical and biological heterogeneity, yet their epigenetic regulation and spatial architecture remain poorly understood. Here, we present an integrative study of NF-PanNETs across multiple tumor grades using single-nucleus ATAC-seq (snATAC-seq) and spatial ATAC-seq. snATAC-seq delineates the chromatin accessibility landscapes of distinct tumor subtypes, immune cells, and cancer-associated fibroblasts (CAFs), revealing key transcription factor (TF) programs that drive tumor progression and shape microenvironmental interactions. Spatial ATAC-seq further identifies two distinct tumor-stroma ecological niches: a proliferative niche marked by MYC and FOX family, and an invasive niche enriched for Snail family TFs and KRAS pathway activity. These findings demonstrate that cellular behavior in NF-PanNETs is governed not only by intrinsic epigenetic states but also by spatial context. Together, our study provides a spatially resolved epigenomic framework for dissecting NF-PanNET heterogeneity and evolution, offering new biomarkers and regulatory axes for molecular stratification and precision therapy.
    DOI:  https://doi.org/10.1101/2025.09.11.675640
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