Abstract

Mesenchymal stem cell (MSC) adipogenesis plays pivotal roles in physiological and pathological contexts, yet remains predominantly induced by biochemical factors in biomedical application. While viscoelastic microenvironments influence MSC fate, prior studies focus on osteogenesis, leaving adipogenic mechanotransduction poorly defined. To address this, we engineered a programmable viscoelastic hydrogel replicating soft tissue mechanics (modulus: 5–700 Pa; relaxation τ 1/2 : 2–170 s). This platform enables on-demand control of adipogenic efficiency through tunable mechano-regulation of the microenvironment, achieving biochemical factor-free differentiation. Mechanistically, biomimetic viscoelasticity upregulates SFRP2, which suppresses Wnt/β-catenin signaling as evidenced by reduced WNT5A and CTNNB1 expression and inhibited β-catenin/YAP1 nuclear translocation. This cascade de-represses PPAR-γ and activates adipogenic programs (C/EBPα/FABP4). Loss-of-function studies also confirm the causal role of SFRP2 in this pathway. Collectively, we uncover a mechanical regulation axis for adipogenesis and establish a tunable material platform for spatially controlled tissue engineering, advancing mechanics-directed regenerative strategies.