Cells communicate mechanically with their local microenvironment, or niche, and these interactions guide developmental processes, direct cell fate, regulate tissue development, and are implicated in the progression of various diseases. We hypothesize that mechanical signals can be used to alter disease progression and directly promote regeneration. This idea is currently being studied in the lab at a variety of levels. At the most basic level, we are studying how externally applied mechanical signals or the mechanics of the cell microenvironment are sensed by cells and are transferred intracellularly (mechanotransduction; Fig. 1). At a more applied level, we are investigating how the effects of mechanics on cell fate or phenotype can be exploited in therapeutic applications.
Figure 1. Cells exert forces and are subject to external forces, which regulate their intracellular signaling pathways. Image taken from (Vining, KH et al., Nature Molecular Cell Biology, 2017).
We are investigating the mechanisms by which mechanical forces and the mechanics of the cellular microenvironment are sensed and how these are converted into biochemical signals. We are exploring this question in a variety of fields including stem cell differentiation and cancer malignancy, as well as understanding the intersection with immune responses and immunotherapies (see Immunotherapy and Immunoengineering section). We are trying to understand the sensitivity of each process to external mechanical forces, the stiffness of the adhesion substrate over different length and time scales, and culture dimensionality (i.e. 2D vs 3D). On the mechanistic side, we are trying to identify individual molecular components or signaling pathways that are important in mediating this responsiveness, with a particular focus on the role of the cytoskeleton and integrins.
Mechanosensing of substrate viscoelasticity:
Cell intrinsic forces are exerted by a cell on its environment of neighboring cells and extracellular matrix, and we are designing biomaterials with independent control over the resistance to these cell-generated forces to precisely guide tissue regeneration. While the field of mechanotransduction has largely focused solely on the role of stiffness, we are particularly focused on the time-dependent mechanical properties (viscoelasticity) of materials. Natural extracellular matrix and tissues are viscoelastic and can be physically remodeled by cell traction forces over time (Fig. 2). We are finding that the stress relaxation of biomaterials regulates many aspects of cell behavior, including spreading, proliferation, and differentiation, and tissue regeneration.
Figure 2. | Biological tissues and extracellular matrices are viscoelastic and exhibit stress relaxation in response to a deformation. Image taken from (Chaudhuri et al., Nature, 2020).
Mechanotherapy with active biomaterials:
Cell extrinsic shear, tensile, or compressive forces regulate many aspects of development and pathology, and we are exploring the ability of external mechanical cues to directly promote regeneration (Fig 3.). Soft robotic devices capable of providing highly controlled and repeatable actuation at the nano to macro-scales are being fabricated and utilized to mechanically stimulate both individual cells in culture and entire tissues in the body in a minimally invasive manner. Light and temperature-sensitive biomaterials are being developed to enable dynamic, spatiotemporal, control over substrate mechanical properties and influence cell behavior. We are finding that appropriate mechanical stimulation can promote regeneration as effectively as stem cell and morphogen-based regenerative strategies.
Figure 3. | Active biomaterial systems offer a wide range of mechanobiology applications and have been used to investigate fibrosis, stem cell differentiation, cell migration, signaling, and muscle regeneration in vitro as well as for in vivo mechanotherapy. Image taken from (Ozkale et al., Biomaterials, 2020).
Altogether, we are developing new systems and approaches to both understand and therapeutically exploit cell-intrinsic and extrinsic mechanical forces for various clinical applications (see Tissue Engineering and Regenerative Medicine, Immunotherapy and Immunoengineering sections).
Relevant review articles in this area
- Chaudhuri, O., Cooper-White, J., Janmey, P.A. et al. Effects of extracellular matrix viscoelasticity on cellular behaviour. Nature 584, 535–546 (2020). https://doi-org.ezp-prod1.hul.harvard.edu/10.1038/s41586-020-2612-2
- Özkale B, Sakar MS, Mooney DJ. Active biomaterials for mechanobiology. Biomaterials. 2021 Jan;267:120497. doi: 10.1016/j.biomaterials.2020.120497.
- Vining KH, Mooney DJ. Mechanical forces direct stem cell behaviour in development and regeneration. Nat Rev Mol Cell Biol. 2017;18(12):728-742. doi:10.1038/nrm.2017.108.
Representative research publications in this area
- Cezar CA, Roche ET, Vandenburgh HH, Duda GN, Walsh CJ, Mooney DJ. Biologic-free mechanically induced muscle regeneration. Proc Natl Acad Sci. 2016;113(6):1534-1539. doi:10.1073/pnas.1517517113.
- Chaudhuri O, Gu L, Klumpers D, et al. Hydrogels with tunable stress relaxation regulate stem cell fate and activity. Nat Mater. 2016;15(3):326-334. doi:10.1038/nmat4489.
- Chaudhuri O, Gu L, Darnell M, et al. Substrate stress relaxation regulates cell spreading. Nat Commun. 2015;6:6365. doi:10.1038/ncomms7365.
- Huebsch N, Lippens E, Lee K, et al. Matrix Elasticity of Void-Forming Hydrogels Controls Matrix elasticity of void-forming hydrogels controls Transplanted Stem Cell-Mediated bone. Nat Mater. 2015;14(12):1-19. doi:10.1038/nmat4407.
- Huebsch N, Arany PR, Mao AS, et al. Harnessing traction-mediated manipulation of the cell/matrix interface to control stem-cell fate. Nat Mater. 2010;9(6):518-526. doi:10.1038/nmat2732.