bims-ecemfi 2026-04-12 papers

J Mater Chem B. 2026 Apr 08.

Stress relaxation timescale and hydrogel network connectivity regulate neural progenitor cell stemness and differentiation.

Lauren E Brown, Daphne Bakker, Ping Zhou, Christopher M Madl.

Neural progenitor cells (NPCs) are promising candidates for cell replacement therapies, yet maintaining stemness while enabling expansion in chemically defined three-dimensional (3D) hydrogels remains a challenge. By tuning crosslink exchange kinetics, crosslinker functionality and stoichiometry, polymer phase separation behavior, and adhesive ligand presentation, a family of hydrogels was prepared to study the effects of stress relaxation timescale and network connectivity on NPC phenotype. Hydrogels with rapid relaxation and low connectivity promote expansion of NPCs as distributed single-cell networks that maintain stemness marker expression and differentiation capacity. NPCs embedded in slowly relaxing hydrogels maintained stemness marker expression through cell clustering but exhibited impaired proliferation and differentiation. Similarly, in the absence of integrin-binding cell adhesive ligands, NPCs also maintained stem cell marker expression but remained as clusters rather than distributed single-cell networks. Cadherin cell-cell contacts enable downstream β-catenin signaling and stemness maintenance, which are enhanced in rapidly relaxing, low connectivity networks. These findings identify a combination of network connectivity, stress relaxation timescale, and integrin-binding adhesive ligands as crucial design parameters for maintaining NPC stemness and differentiation capacity in 3D hydrogel networks.

DOI: https://doi.org/10.1039/d5tb02537k

Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2520717123

Amoeboid-mesenchymal transition and the proteolytic control of cancer invasion plasticity.

Adam W Olson, Jonathan Li, Xiao-Yan Li, Lana King, Long Jiang, Kalins Banerjee, Atticus J McCoy, Mahnoor N Gondal, Arul M Chinnaiyan, Dorraya El-Ashry, Evan T Keller, Andrew J Putnam, Stephen J Weiss.

Invasion plasticity allows malignant cells to toggle between collective, mesenchymal, and amoeboid phenotypes while traversing extracellular matrix (ECM) barriers. Current dogma holds that collective and mesenchymal invasion programs trigger the mobilization of proteinases that digest structural barriers dominated by type I collagen, while amoeboid activity allows cancer cells to marshal mechanical forces to traverse tissues independently of ECM proteolysis. Here, we use cancer spheroid-3-dimensional matrix models, single-cell RNA sequencing, and human tissue explants to identify the mechanisms controlling mesenchymal versus amoeboid invasion. Unexpectedly, collective/mesenchymal- and amoeboid-type invasion programs-though distinct-are each characterized by active tunneling through ECM barriers, with expression of matrix-degradative metalloproteinases. CRISPR/Cas9-mediated targeting of a single membrane-anchored collagenase, MMP14/MT1-MMP, ablates tissue-invasive activity while coregulating cancer cell transcriptional programs. Though changes in matrix architecture, nuclear rigidity, and metabolic stress as well as the presence of cancer-associated fibroblasts are proposed to support amoeboid activity, none of these changes restore invasive activity of MMP14-targeted cancer cells. While a requirement for MMP14 is bypassed in low-density collagen hydrogels, invasion by the proteinase-deleted cells is associated with nuclear envelope and DNA damage, highlighting a proteolytic requirement for maintaining nuclear integrity. Nevertheless, when cancer cells confront explants of live human breast tissue, MMP14 is again required to support invasive activity. Corroborating these results, spatial transcriptomic and immunohistological analyses of human breast cancers identified MMP14 expression in tissue-infiltrating carcinoma cells that were further juxtaposed with proteolyzed type I collagen fragments, underlining the pathophysiologic importance of this proteinase in directing invasive activity in vivo.

Keywords: amoeboid; cancer; invasion; proteinase

DOI: https://doi.org/10.1073/pnas.2520717123

bioRxiv. 2026 Apr 02. pii: 2026.03.31.715527. [Epub ahead of print]

Physical continuity at biomaterial-ECM interfaces regulate fibroblast activation via NF-κB.

Alejandra Suarez-Arnedo, Michaela Harris, Calista Robinson, Lindsay Riley, Amy Kim, Lucy Zhang, Brenton D Hoffman, Tatiana Segura.

Fibrotic responses at biomaterial-tissue interfaces limit implant integration and regenerative healing, yet how the interaction between biomaterials and the extracellular matrix (ECM) regulates fibroblast activation remains poorly understood. Granular hydrogels including microporous annealed particle scaffolds (MAP) reduce fibrosis, while chemically and mechanically matched hydrogels do not, suggesting a dominant role for scaffold architecture. In this model, MAP scaffolds allow collagen infiltration and form physically continuous composites, whereas hydrogels exclude collagen and generate interfacial slip planes. To isolate how biomaterial architecture influences extracellular matrix (ECM) integration and fibroblast activation, we developed a reductionist in vitro model that integrates collagen type I with either microporous annealed particle (MAP) scaffolds or chemically and mechanically matched bulk hydrogels. This physical integration stabilizes collagen architecture, limits fibroblast-mediated matrix compaction, suppresses contractility, and attenuates myofibroblast transition. Fibroblasts in mechanically integrated environments exhibit reduced expression and nuclear localization of NF-κB and are enriched for quiescent phenotypes. Together, these findings identify biomaterial-ECM physical continuity as a design principle for limiting fibrotic signaling.

DOI: https://doi.org/10.64898/2026.03.31.715527

Adv Mater. 2026 Apr 09. e23440

Tough and Rapidly Relaxing Hydrogels Via Programmable Crosslink Kinetics.

Yuanyuan Wei, Stephen J K O'Neill, Jade A McCune, Oren A Scherman.

Replicating the synergy of high toughness and rapid stress relaxation found in native tissues remains a central challenge for synthetic hydrogels on account of their intrinsic mechanical-temporal trade-off. Here we introduce a supramolecular hydrogel platform that leverages kinetic programming to precisely regulate crosslink dynamics through molecular dissociation kinetics. This molecular design allows independent tuning of relaxation dynamics and fracture toughness, decoupling properties that are typically correlated. The resulting hydrogels exhibit stress relaxation ( t1/2${t}_{1/2}$ = 0.1-100 s) two orders of magnitude faster than conventional networks while achieving exceptional fracture energy ( Gc=14,500Jm-2$G_c = 14{,}500\,\mathrm{J\,m^{-2}}$ ), well above natural rubber. Slowing crosslink dissociation significantly enhances energy dissipation under load, revealing a kinetic principle for toughening viscoelastic networks. This work establishes a molecular blueprint for designing soft materials with programmable, time-dependent mechanics.

Keywords: kinetic programming; programmable time‐dependent mechanics; stress relaxation dynamics; supramolecular hydrogels; toughness

DOI: https://doi.org/10.1002/adma.202523440

bioRxiv. 2026 Apr 02. pii: 2026.03.31.715459. [Epub ahead of print]

Synthetic budding morphogenesis by optogenetic receptor tyrosine kinase signaling.

Louis S Prahl, Ronald Canlla, Aria Zheyuan Huang, Daniel S Alber, Sandra L Shefter, Sachin N Davis, Samuel H Grindel, Zikang Dennis Huang, Thomas R Mumford, William Benman, Lukasz J Bugaj, Kyle W McCracken, Alex J Hughes.

The mammalian kidney relies on a branched network of collecting ducts for fluid transport and homeostasis. Replicating this network in vitro would parallelize function in synthetic replacement kidneys, yet current organoids have limited branching capacity. Here, we establish a developmentally-informed strategy to control organoid budding through optogenetic control of a receptor tyrosine kinase, RET. We first show pharmacological manipulation of RET signaling controls the extent of branching in mouse embryonic kidneys and human stem cell-derived kidney organoids. Next, we develop an optogenetic RET receptor (optoRET) that signals in a ligand-independent manner via blue light-mediated clustering. Epithelial cells expressing optoRET reproduce stereotyped RET signaling, scattering, and symmetry breaking in response to blue light. Human kidney organoids undergo budding with controllable orientation in response to spatially patterned optoRET stimulation. Our results establish ligand-free optogenetic control of branching and inspire new synthetic biology strategies for epithelial organoid design.
Highlights: GDNF-RET controls branching and tip cell state in mouse and human kidney tissues.OptoRET reproduces endogenous RET signaling and morphogenesis in cell lines.OptoRET enables ligand-free budding in human renal epithelial organoids.Spatially patterned optoRET stimulation controls budding orientation.

DOI: https://doi.org/10.64898/2026.03.31.715459