Mechanochemical regulation of organoid morphogenesis: Integrated signaling circuits in engineered microenvironments

Organoid morphogenesis is orchestrated by complex mechanical interactions between cells and their microenvironment. Recent evidence highlights the critical role of mechanical stimuli—including fluid shear stress, axial tensile and compressive forces, extracellular matrix (ECM) stiffness, and viscoelasticity—in integrating through specialized mechanotransduction hubs to regulate spatial and temporal morphogenetic programs. These mechanical cues are decoded by interconnected signalling architectures, including the MAPK/PI3K–Akt pathways mediating fluidic forces, the Wnt/β-catenin and Hippo–YAP/TAZ cascades responding to axial forces and ECM rigidity, and the integrin–β1–tensin-1–YAP axis interpreting ECM viscoelastic properties. These interconnected networks establish hierarchical control over organoid proliferation, lineage specification, and tissue patterning across diverse culture systems, spanning static elastic substrates to dynamic viscoelastic matrices with tunable stress relaxation profiles. Beyond cytoplasmic signalling, emerging studies identify nuclear mechanotransduction as a central integrative layer that converts mechanical inputs into stable transcriptional and epigenetic outcomes. Mechanical forces transmitted via the cytoskeleton–LINC complex reshape nuclear mechanics through Lamin A–dependent regulation of nuclear stiffness, directly remodel chromatin accessibility, and modulate mechanosensitive transcriptional regulators. Through this nucleus-centred mechanism, transient mechanical cues are encoded as persistent gene expression programmes that govern cell fate specification, tissue layering, and functional compartmentalisation in organoids. This review systematically maps the mechanobiological logic underlying organoid development across three analytical dimensions: molecular decoding of mechanical inputs, cellular-scale integration of mechanotransduction signals, and emergent tissue-level patterning. By elucidating self-reinforcing feedback loops between matrix biophysics, nuclear mechanics, and chromatin organisation, we propose an engineering framework for designing biomimetic microenvironments. This approach enables the development of next-generation organoid platforms with enhanced architectural fidelity and physiological relevance, particularly through spatiotemporal control of viscoelastic memory and dynamic mechanical conditioning. • Organoid development, homeostasis, and regeneration are governed by the integration of cell-intrinsic nuclear mechanics and cell-extrinsic mechanical forces. • Mechanical stimuli drive organoid morphogenesis through coordinated activation of MAPK, PI3K–Akt, Wnt/β-catenin, Hippo–YAP/TAZ pathways and nuclear mechanotransduction mechanisms. • Nuclear mechanotransduction converts mechanical cues into stable transcriptional and epigenetic states via Lamin A–dependent nuclear mechanics and chromatin remodelling. • Synthetic matrices enable precise spatiotemporal control of fluid shear stress, axial forces, ECM stiffness, and viscoelasticity, providing a platform to engineer nuclear mechanical conditioning and tissue-level patterning.