"To our knowledge, this is the first ECM model that allows researchers to study T cells with stiffness from viscoelasticity decoupled, and thus enables us and others in the future to investigate how immune and other cells might be mechanically regulated," said co-first author Yutong Liu, Ph.D., who was a graduate student in Mooney's group. The resulting ECM-mimicking hydrogels equally allowed the attachment of pre-activated T cells but, importantly, enabled their stimulation with specific mechanical signals. More highly cross-linked collagen molecules produced more elastic hydrogels. Independently, viscoelasticity became tunable by varying the amounts of a synthetic cross-linker molecule that further networked the collagen molecules. To mimic natural collagen-based ECM, the team fabricated hydrogels whose stiffness they could tune by varying the concentration of collagen molecules: fewer numbers of collagen molecules produced lower stiffness and higher numbers, higher stiffness. An ECMs stiffness depends on how densely it is packed with collagen molecules, whereas its distinct viscoelasticity depends on how densely collagen molecules are cross-linked to each other. Each fibril can be considered a mechanical spring, and each fiber as an assembly of springs. Individual collagen protein molecules are naturally organized into crimped fibrils that aggregate further into fibers by chemically cross-linking themselves. Collagen is a major ECM protein secreted by almost all cells in the body. Key to their discoveries was the team's engineering of a tunable ECM model, in which they focused on a type of collagen that they found to be key to dictating the mechanical behavior of different tissues. "Our study provides a conceptual basis for future strategies aiming to create functionally distinct T cell populations for adoptive therapies by selectively tuning mechanical input provided by biomaterials-based engineered cell culture systems." Pinkas Family Professor of Bioengineering at SEAS, and leads the Wyss Institute's Immunomaterials Initiative. "Importantly, the phenotypes, functions, and gene expression programs of T cells trained in variations of the system correlated well with those we found in T cells in mechanically distinct tissues from patients with cancer or fibrosis," said Mooney who also is the Robert P. Explained in physical terms, a viscous (fluid) material, like honey, is more likely to flow, while an elastic (solid) material returns more rapidly to its original shape, like a rubber band after stretching - and this holds true for tissues which are composed of both solid and fluid components. Mechanical resistance comes in the form of "stiffness," a tissue's (or any material's) resistance to instantaneous deformation, and "viscoelasticity," the type of relaxation it exhibits over time following its deformation. The findings are reported in Nature Biomedical Engineering. This enabled them to demonstrate a distinct impact of tissue viscoelasticity on T cell development and function in vitro and in vivo, and to identify a molecular pathway driving the phenomenon. By engineering a 3-dimensional model of the extracellular matrix (ECM), produced by cells that are responsible for tissues' different stiffnesses and viscoelasticities, they were able to tune both parameters independently. Paulson School of Engineering and Applied Sciences (SEAS), led by Wyss Core Faculty member David Mooney, Ph.D., took a novel biomaterials approach to investigate the effect of tissue mechanics on the state of T cells. Now, a research team at the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard John A. The mechanical features of tissues, for example, bone, muscle, different internal organs, and blood, can vary widely, and pathological tissues such as tumor masses or fibrotic tissues are mechanically significantly different from healthy tissues. One way to approach this goal is to better understand how T cells' traits and functions, including their cytotoxic effects on unwanted target cells (effector T cells) or their ability to recall and eliminate them if they show up again (memory T cells), are shaped by the mechanical resistance of the tissues they encounter while infiltrating them. But improving the ability to create patient-specific T cell populations with specific traits and functions could broaden clinicians' repertoire of T cell therapies. The successful campaign of adoptive T cell therapies, a type of immunotherapy in which immune T cells are collected from a patient, enhanced outside of the body, and reinfused back into the same patient, especially against blood cancers is well under way.
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