Defining the role of linear and nonlinear forces in regulating cell metabolism

The extracellular matrix (ECM) provides essential tissue infrastructure and mechanical cues that regulates cell metabolism. Mechanotransduction is the conversion of mechanical forces from the ECM to intracellular chemical signals and plays a vital role in health and disease through cell-matrix interactions. While evidence supports a ‘mechano-metabolic link’ between mechanotransduction and metabolism, the precise pathway connecting ECM mechanical states to cellular metabolism remains poorly understood due to the ECM’s complexity, including its viscoelastic properties, which exhibit both strain-independent (linear) and strain-dependent (nonlinear) regimes. All tissues exhibit both linear and nonlinear viscoelasticity, typically reported as stiffness and strain-stiffening, respectively; however, a fundamental gap remains in understanding how these distinct mechanical properties counterbalance each other to regulate cell metabolism. Key open questions include how cells engage with nonlinear viscoelastic environments, how mechanotransduction scales with cell and tissue maturity, and how nonlinear viscoelasticity influences cellular uptake and consumption of metabolic biomolecules. To address these gaps, this proposal uses primitive and differentiated induced pluripotent stem cells (iPSCs), both as single-cell and organoid cultures, in a 3D in vitro polymeric hydrogel systems to independently present cell-accessible and cell-inaccessible nonlinear viscoelastic regimes. We combine this with material- and omics-based modeling approaches to define viscoelastic and metabolic signaling regimes. In Project 1, we will use ECM ligand-binding motifs and both primary cells and iPSCs to investigate integrin-mediated cell-matrix interactions across viscoelastic regimes, cell maturity, and tissue complexity. In Project 2, we will examine how nonlinear viscoelasticity influences cellular uptake of metabolic precursors such as lipids and apply model-based approaches to define characteristic metabolic and proteomic signatures associated with linear and nonlinear regimes. The outcomes of this proposal will advance our understanding of mechanosignaling in nonlinear viscoelastic environments and establish a mechanistic model of the mechanical regulation of cellular metabolism. The long-term goal of the lab is to develop complex in vitro models to investigate how physiological processes such as aging and pregnancy induce systemic tissue alterations that drive changes in cell-matrix interactions and mechanosignaling, ultimately influencing cell and tissue function. By uncovering a direct mechano-metabolic connection, this work will have broad implications for fundamental biology while also developing critical tools and workflows for studying cell-matrix interactions. Importantly, while this proposal focuses on fundamental biological processes, the methods and tools developed will be broadly applicable across various cell, tissue, and disease states. Project Number: 1R35GM162844-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Aidan Gilchrist | Institution: UNIVERSITY OF CALIFORNIA AT DAVIS, DAVIS, CA | Award Amount: $432,417 | Activity Code: R35 | Study Section: Special Emphasis Panel[ZRG1 MCST-Q (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11271962