Jung, W.-H. | Search bioRxiv

bioRxiv2025

Matrix viscoelasticity regulates dendritic cell migration and immune priming

The tumor microenvironment shapes immune surveillance through its mechanical properties, yet the role of matrix viscoelasticity remains unclear. Here, we used a collagen system with tunable viscoelasticity to define how matrix relaxation directs dendritic cell (DC) behavior. Elastic matrices impaired DC migration by limiting actomyosin-driven collagen remodeling, thereby reducing DC-T cell encounters and weakening T cell priming, activation, proliferation, and tumor killing. Blocking DC migration in fast-relaxing gels recapitulated key aspects of the impaired T cell priming seen in elastic matrices. Prolonged confinement in elastic extracellular matrix induced a mechanomemory state, locking DCs into reduced motility even after transfer to viscoelastic environments, corresponding to altered chromatin accessibility. Finally, studies with patient-derived ependymoma samples confirmed these findings, identifying viscoelasticity as a barrier to antitumor immunity with implications for therapeutic intervention.

bioengineering↗

bioRxiv2025

Human progenitor T-cell differentiation regulated by the mechanical resistance of thymus-mimetic extracellular matrices

Therapeutic T-cell engineering ex vivo from human hematopoietic stem cells (HSCs) focuses on recapitulating notch1-signaling and 4{beta}1-integrin-mediated adhesion within the thymic niche with supportive stromal cell feeder-layers or surface-immobilized recombinant protein-based engineered thymic niches (ETNs). The relevant Notch1-DLL-4 and 4{beta}1-integrin-VCAM-1 interactions are known to respond to mechanical forces that regulate their bond dissociation behaviors and downstream signal transduction, yet manipulating the mechanosensitive features of these key receptor-ligand interactions in thymopoiesis has been largely ignored in current ETN designs. Here, we demonstrate that human T-cell development from cord blood-derived CD34+ HSCs is regulated via molecular cooperativity in notch1 and integrin-mediated mechanotransduction. Mechanically confining interpenetrating network (IPN) hydrogel-based 3D cell culture comprised of collagen type I and alginate polysaccharides functionalized with DLL-4 and VCAM-1 is used as a model viscoelastic 3D ETN to manipulate human progenitor (pro)T-cell differentiation. This ETN enables orthogonal control of the mechanical and biomolecular features of the thymic niche, including thymopoietic ligand density, modulus, and viscoelastic properties (e.g., stress relaxation kinetics). We identify that soft, viscous matrices that enhance activation of the notch1-pathway, and subsequently notch1 intracellular domain (NICD) nuclear import sustain the T-cell development gene regulatory network during proT-cell differentiation. Conversely, stiff, elastic matrices inhibit HSC commitment to the T-lineage, and rather promotes Myeloid-cell differentiation. Our observations indicate mechanical reciprocity in signaling pathways indispensable to thymopoiesis, and highlights extracellular matrix mechanics as a variable in controlling hematopoietic stem cell fate decisions.

bioengineering↗