bims-ecemfi 2026-08-30 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2026–08–30
eight papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

Matrix Metalloproteinase-Mediated Degradation Governs Angioarchitecture within Poly(ethylene Glycol) Hydrogels.
Sequential Patterning of Photoresponsive Hydrogels Directs Crypt Fission and Reveals the Role of Epithelial Curvature on Fission Symmetry.
Form, Force, and Fate: The Biological Language of Curvature.
Engineering Tissue-Relevant Collagen Bundle Architectures via Macromolecular Crowding.
Agarose-Based 3D Invasion Assay for Simultaneous Quantification of Tumor Cell Invasion and Extracellular Matrix Degradation.
Long-lasting extracellular matrix modifications reshape intestinal stem cell fate and promote chronic inflammation.
Cooperation, Defection, and Collapse: A Multiscale Game Theory Framework for Emphysema Progression.
Tracking breast cancer progression using Methylscape.

Acta Biomater. 2026 Aug 27. pii: S1742-7061(26)00578-7. [Epub ahead of print]

Matrix Metalloproteinase-Mediated Degradation Governs Angioarchitecture within Poly(ethylene Glycol) Hydrogels.

Kevin C Ling, Aly March, Yingjie Wu, Annika Deans, Jordan Jones, E Thomas Pashuck, Danielle S W Benoit.

  Current tissue engineering strategies struggle to recapitulate the full diversity of tissue-specific vascular niches. Here, matrix metalloproteinase (MMP)-degradable poly(ethylene glycol) (PEG) hydrogels are used to define design principles governing vascular morphogenesis. Vasculogenesis was modeled by encapsulating human umbilical vein endothelial cells (HUVECs) in PEG hydrogels co-cultured with human mesenchymal stem cells (hMSCs), enabling the formation of 3D vessel networks over two weeks. Angiogenesis was modeled by entrapping HUVEC-hMSC spheroids within PEG hydrogels and assessing endothelial sprouting behavior. In parallel, comparative kinetic parameters for peptide degradation were calculated for vasculogenic (kvasc) and angiogenic (kang) conditions; kvasc values for IPES↓LRAG (8.8 × 10-7 hr-1 cell-1) and VPLS↓LYSG (1.4 × 10-6 hr-1 cell-1) were three-to-five-fold higher than GPQG↓IWGQ (2.9 × 10-7 hr-1 cell-1), indicating greater relative susceptibility to vasculogenic proteolysis. Consistent with these results, HUVECs encapsulated in hydrogels crosslinked with IPES↓LRAG or VPLS↓LYSG formed vessel networks with over two-fold greater diameter, length, and density compared to networks formed in GPQG↓IWGQ-crosslinked hydrogels under vasculogenic conditions, driven by greater overall degradability. In contrast, degradability influenced early sprouting dynamics under angiogenic conditions but did not affect overall network development. Additionally, vascular networks formed in non-degradable and GPQG↓IWGQ-crosslinked hydrogels exhibited compensatory upregulation of MMP and tissue inhibitor of metalloproteinase (TIMP) expression. Together, these findings elucidate how engineered extracellular matrix (eECM) degradability regulates vascular morphogenesis via cellular proteolytic feedback mechanisms, establishing a framework for designing eECM biomaterials that support tissue-specific microvascular modeling and improved vascular engraftment for regenerative medicine. STATEMENT OF SIGNIFICANCE: The microvasculature supplies nutrients and oxygen to nearly all tissues, yet current tissue engineering approaches struggle to recapitulate the diversity of tissue-specific vasculature. Poly(ethylene glycol) (PEG) hydrogels crosslinked with enzymatically degradable peptides were used to investigate how extracellular matrix degradability directs vessel development under vasculogenic and angiogenic conditions. Peptide crosslinkers with higher degradability promoted the formation of vessel networks with increased diameter, density, and length in vasculogenic conditions. Under angiogenic conditions, degradability regulated early sprouting without altering network properties. Additionally, the expression of matrix metalloproteinases and their inhibitors was elevated in slowly- or non-degradable hydrogels, suggesting a cellular attempt to overcome matrix constraints. These findings establish a biomaterial design strategy to engineer tissue-specific vasculature for disease modeling and regenerative medicine.

Keywords:  Angiogenesis; Engineered extracellular matrix (eECM); MMP-degradable PEG hydrogels; Microvascular morphogenesis; Vasculogenesis

DOI:  https://doi.org/10.1016/j.actbio.2026.08.048
Adv Sci (Weinh). 2026 Aug 29. e77397

Sequential Patterning of Photoresponsive Hydrogels Directs Crypt Fission and Reveals the Role of Epithelial Curvature on Fission Symmetry.

Delaney L McNally, Kaustav Bera, Nolan R Petrich, Alex Khang, Marilyne Coulombe, David Castillo-Azofeifa, Ophir D Klein, Peter J Dempsey, Kristi S Anseth.

  Fission increases the number of crypts in the intestine during neonatal growth and also restores crypt density after injury by bifurcation of a pre-existing parent crypt into daughter crypts. While fission is typically symmetric in healthy crypts, it is more asymmetric in diseases, and the relationship between parent crypt shape and daughter crypt (a)symmetry is difficult to study as crypt budding and fission are stochastic in organoid models and difficult to control in vivo. Here, a photoresponsive hydrogel is introduced to spatiotemporally control daughter crypt emergence from mature parent crypts in intestinal organoids, enabling longitudinal tracking of crypt bifurcation in vitro. Variation of the photopatterned dimensions tunes parent crypt shape and reveals that both fission efficiency and crypt symmetry depend on parent crypt geometry. Epithelial boundary analysis identified parent crypt curvature as a key factor influencing daughter crypt symmetry. High-curvature or narrow crypts yielded symmetric daughter crypts, whereas wider parent crypts with lower epithelial curvature generated progressively more asymmetric crypts. Mechanistically, non-muscle myosin IIA acts as one key regulator of crypt symmetry. Overall, this work introduces a reproducible and spatiotemporally controllable in vitro model of crypt fission, allowing identification of mechanical determinants of fission that influence intestinal regeneration and development.

Keywords:  crypt fission; hydrogels; myosin; organoids; photodegradation; photopatterning; tissue regeneration

DOI:  https://doi.org/10.1002/advs.77397
Adv Healthc Mater. 2026 Aug 28. e71564

Form, Force, and Fate: The Biological Language of Curvature.

Diana Jesus, Syeda M Bakht, João F Mano.

  Across scales and dimensions, curvature is an intrinsic feature of living systems that regulates cellular behavior in both health and disease. Recent advances in mechanobiology have established curvature as a bioactive physical cue capable of driving cellular functions and linking form, force, and fate. In this perspective, we highlight how curvature manifests across biological length scales and shapes key cellular processes such as migration and differentiation. We discuss emerging mechanisms of curvature sensing and transduction, outlining open questions regarding their integration within native and engineered environments. Finally, we reflect on current and future advances in curvature-guided biomaterial design, their impact on tissue engineering, and the potential of curvature as a biophysical marker in physiological and pathological contexts.

Keywords:  biomaterials; curvature; curvotaxis; decision‐making; geometry; mechanobiology

DOI:  https://doi.org/10.1002/adhm.71564
Adv Healthc Mater. 2026 Aug 25. e71566

Engineering Tissue-Relevant Collagen Bundle Architectures via Macromolecular Crowding.

Xiangyu Gong, Zixie Liang, Yaqing Huang, Raymond Liu, Zihan Zhou, Yair Saucedo, Zhang Wen, Alejandro Rossello-Martinez, Mahdi Karimi, Lingjie Pan, Themis R Kyriakides, Michael Mak.

  Collagen type I forms thick, cell-scaled bundles in native tissues, but standard in vitro collagen gels are composed of disordered thin nanofibrillar networks lacking this architecture. We introduce a simple macromolecular crowding (MMC) strategy, distinct from thermo- or pH-driven gelation, that rapidly assembles collagen into continuous, thick, microscale bundles with tunable dimensions matching healthy and diseased tissue states. These bundles recreate fibrotic and cancer-associated matrix features, enabling direct investigation of how the geometry and topography of collagen fiber networks regulate cell-state transitions and tumor invasion. The method is compatible with collagen from multiple species and collagen-rich decellularized ECM. These single-cell-sized bundles also support robust endothelial sprouting and the formation of aligned microvascular networks in matrices that normally restrict angiogenesis. Bundle suspensions are readily extrudable for bioprinting and injectable delivery applications. Compared to conventional collagen gels, MMC-synthesized bundles are highly tunable to trigger diverse cell behaviors and more accurately replicate native tissue microenvironments, providing a broadly applicable platform for disease modeling and regenerative engineering.

Keywords:  collagen architectures; collagen bioprinting; extracellular matrices; injectable materials; macromolecular crowding; tissue engineering

DOI:  https://doi.org/10.1002/adhm.71566
Methods Protoc. 2026 Jul 28. pii: 112. [Epub ahead of print]9(4):

Agarose-Based 3D Invasion Assay for Simultaneous Quantification of Tumor Cell Invasion and Extracellular Matrix Degradation.

Andreas R Thomsen, Pascaline Kouam-Daniel, Bettina Priesch-Grzeszkowiak, Anja Grillenberger, Sandra Kumbruch, Ali H Acikelli, Helmut Bühler, Christian Baues.

  Tumor cell invasion is a critical step in local tumor progression, recurrence, and metastasis. Conventional two-dimensional migration assays and many existing three-dimensional invasion models often assess cell migration, invasion into the extracellular matrix and matrix degradation as separate endpoints, although these processes are tightly coupled in vivo. Therefore, robust and reproducible in vitro models are needed to investigate tumor cell invasion under defined extracellular matrix conditions. We developed an agarose-based three-dimensional invasion assay, termed the Freiburg 3D invasion assay, for the simultaneous analysis of tumor cell migration, invasion, and extracellular matrix degradation. The system consists of a 2.8% agarose matrix containing defined microcavities connected by a common loading channel. Tumor cells are seeded into these microcavities, where they form compact cell aggregates. The cavities are subsequently filled with collagen type I or extracellular matrix gel. After polymerization, the matrix-containing agarose strips are transferred into parking pockets, cultured for several days, and monitored by microscopy. Invasion distance, single-cell migration, and ECM-cleared area are quantified from serial microscopic images using image analysis software. The system distinguished weakly invasive MCF7 breast cancer cells from highly invasive MDA-MB-231 cells. In addition, treatment with a protease inhibitor and irradiation reduced tumor cell invasion and extracellular matrix remodeling, demonstrating the suitability of the assay for pharmacological and radiation-response studies. The Freiburg 3D invasion assay provides a practical and reproducible three-dimensional in vitro model for analyzing tumor cell invasion and protease-associated extracellular matrix degradation.

Keywords:  3D invasion assay; agarose; extracellular matrix; matrix degradation; tumor invasion

DOI:  https://doi.org/10.3390/mps9040112
Immunity. 2026 Aug 26. pii: S1074-7613(26)00321-3. [Epub ahead of print]

Long-lasting extracellular matrix modifications reshape intestinal stem cell fate and promote chronic inflammation.

Idan Adir, Carmel Sochen, Sivan Gelb, Aviya Habshush Menachem, Sacha Lebon, Barak Toval, Vladyslav Holiar, Natalia Davidzohn, Tomer-Meir Salame, Irit Rosenhek-Goldian, Simonas Savickas, Fabio Sabino, Valerio Izzi, Bella Ungar, Alon Abend, Inna Solomonov, Ehud Zigmond, Taina Pihlajaniemi, Ulrich Auf dem Keller, Moshe Biton, Irit Sagi.

  Tissue regeneration is viewed as a return to homeostasis, but whether the extracellular matrix (ECM) reverts during recovery from gut inflammation is unclear. Using temporal multi-omics, biomechanical profiling, and spatial fate mapping in colitis models, we showed that colonic ECM underwent lasting pathological reprogramming following inflammation, which we termed modified (mod)ECM. Characterized by collagen XVIII accumulation and immune-driven proteolysis, modECM redirected intestinal stem cells (ISCs) toward a wound-associated epithelial state with a pro-inflammatory transcriptional program. Ex vivo, modECM alone reshaped ISC fate by suppressing Wnt signaling and activating immune recruitment pathways. In vivo, modECM-rich zones sustained T cell infiltration and KRT14+ epithelial cell emergence from Lgr5+ progenitors. This aberrant epithelial program was mirrored in inflamed rectal biopsies from individuals with ulcerative colitis. Our findings redefine the ECM as a long-lived instructive compartment that encodes injury memory and promotes maladaptive regeneration, positioning it as a therapeutic target in chronic inflammatory diseases.

Keywords:  ECM; ECM remodeling; ISC; T cell recruitment; collagen XVIII; colon; extracellular matrix; intestinal stem cell; pathological reprogramming; tissue regeneration; wound-associated epithelia

DOI:  https://doi.org/10.1016/j.immuni.2026.07.022
Cells. 2026 Aug 17. pii: 1470. [Epub ahead of print]15(16):

Cooperation, Defection, and Collapse: A Multiscale Game Theory Framework for Emphysema Progression.

Jerome Cantor.

  In the current paper, pulmonary emphysema is hypothesized to emerge from a nonlinear breakdown of cooperation across two tightly coupled systems: the extracellular matrix (ECM) crosslink network and the cellular populations responsible for its maintenance. To formalize this concept, we construct a game-theoretic model that unifies the mechanical failure, inflammatory changes, and percolation-driven tissue collapse that are recognized features of the disease. At the ECM level, elastin and collagen crosslinks are modeled as players in an iterated Prisoner's Dilemma, where cooperation corresponds to maintaining structural integrity, and defection corresponds to rupture under mechanical stress. At the cellular level, fibroblasts, macrophages, and neutrophils engage in a parallel strategic game in which repair reflects cooperative activity, and protease- or oxidant-producing phenotypes are indicative of defection. These parallel games are coupled through bidirectional payoff modulation, generating a dynamical system with bistability, tipping points, and runaway positive feedback. As the fraction of intact crosslinks falls below a critical percolation threshold, global network connectivity collapses and lung function drops precipitously. This framework explains the characteristic features of pulmonary emphysema, including spatial heterogeneity, abrupt acceleration, and irreversibility as emergent properties of coupled cooperation-defection dynamics, and identifies new leverage points for stabilizing cooperation and preventing catastrophic network failure in early disease. In support of this hypothesis, we present previously published studies from our laboratory involving measurements of elastin-specific desmosine crosslinks in human postmortem emphysematous lungs showing a marked increase in tissue crosslink density at the early stage of the disease, and accelerating loss of these crosslinks as airspace enlargement progresses, consistent with initial cooperation followed by defection. This conceptual framework is then applied to the poorly understood lung disease, Combined Pulmonary Fibrosis and Emphysema, to provide a potential mechanism for its pathogenesis.

Keywords:  combined pulmonary fibrosis and emphysema; extracellular matrix crosslinking; game theory; percolation theory; pulmonary emphysema

DOI:  https://doi.org/10.3390/cells15161470
Sci Adv. 2026 Aug 28. 12(35): eaeb6556

Tracking breast cancer progression using Methylscape.

Zhen Zhang, Emtiaz Ahmed, Nicolas Constantin, Jennifer Lu, Stephanie Portelli, David B Ascher, Darren Korbie, Alain Wuethrich, Abu Ali Ibn Sina, Matt Trau.

Cancer progression is driven by epigenetic reprogramming, where promoter hypermethylation of tumour-suppressor genes and global hypomethylation reshape gene regulation and cellular phenotypes, promoting oncogenesis and disease advancement. We previously introduced the Methylscape, a cancer-specific DNA methylation landscape characterized by clustered promoter hypermethylation and gene body hypomethylation that enhances DNA's physical affinity for gold surfaces. Here, we demonstrate that Methylscape can be leveraged to monitor cancer progression. In a TGF-β-induced breast cancer epithelial-mesenchymal transition (EMT) model, we observe increased Methylscape enrichment of mesenchymal-state DNA, indicating that this method can sensitively detect subtle epigenetic remodelling linked to tumour progression. Using a gold-based DNA desorption enrichment strategy coupled with methylation sequencing and qPCR, we show that hypermethylated regions are preferentially enriched on gold surface. Finally, we developed a low-cost, disposable screen-printed electrode platform for stage-specific breast cancer monitoring. Together, these findings establish Methylscape as a promising biophysical biomarker for non-invasive, real-time monitoring of cancer progression, advancing its potential for clinical translation.

DOI: https://doi.org/10.1126/sciadv.aeb6556