Mechanics dictate stromal cell – ECM dynamic interactions: studies using organ-derived ECM hydrogels
Mechanics dictate stromal cell – ECM dynamic interactions: studies using organ-derived ECM hydrogels
This thesis Fenghua Zhao investigates how the mechanical properties of the extracellular matrix (ECM) influence cellular behaviors such as differentiation, matrix remodeling and vascularization, particularly in the context of fibrotic diseases and wound healing. Organ-derived ECM hydrogels were developed as advanced 3D culture systems that closely mimic native tissue mechanics, enabling the observation of cell–matrix interactions.
Through comparative studies of hydrogels derived from different organs, it was found that skin-derived ECM effectively promoted vascular network formation, underscoring the dominant role of ECM mechanics over biochemical composition in supporting angiogenesis. Fibroblasts were shown to dynamically interact with endothelial cells, modifying the ECM microenvironment to facilitate vessel formation.
By tuning ECM stiffness using ruthenium crosslinking, we demonstrated that increased matrix stiffness promoted myofibroblastic differentiation of fibroblasts in 2D cultures. In 3D culture systems, a stiffness gradient influenced fibroblast orientation and induced distinct ECM remodeling patterns across different stiffness zones. Additionally, umbilical cord-derived mesenchymal stem cells also exhibited stiffness-dependent remodeling behaviors. These responses were partially regulated by the mechanosensitive ion channel Piezo1, which influenced matrix contraction and degradation in a stiffness-specific manner.
Together, this work provides new mechanistic insights into how ECM mechanics influence cell fate and function. It introduces versatile in vitro models for studying fibrotic microenvironments and highlights Piezo1 as a potential therapeutic target. The findings lay the foundation for developing antifibrotic and regenerative strategies tailored to the biomechanical properties of diseased tissues.