Integrating biochemical cues and mechanical forces in stem cell-epithelial differentiation

Epithelial differentiation from stem cells is fundamental to regenerative medicine, with applications ranging from skin repair to epithelial tissue engineering. While traditionally guided by biochemical regulators such as retinoic acid (RA) and growth factors, the mechanical microenvironment is a critical, yet often underrepresented regulator of epithelial fate. This review addresses the knowledge gap by examining how chemical and mechanical cues cooperate to guide epithelial commitment across both conventional two-dimensional (2D) and advanced three-dimensional (3D) culture models. We specifically focus on the mechanism of mechanotransduction, detailing how mechanical forces are converted into biochemical signals. This process relies on specialized mechanosensitive mediators such as focal adhesion, ion channels, and cell-cell adhesion molecules. These inputs converge on the central Hippo-YAP/TAZ transcriptional hub, which acts as the primary mechanical sensor to modulate lineage trajectories. This integration reshapes how cells interpret signals through the major regulatory network (WNT, Notch, and TGFβ pathways) while balancing stemness against epithelial differentiation. Addressing this integrated mechanobiological perspective is essential for improving mechanistic understanding and reproducibility in stem cell-epithelial differentiation protocols. Incorporating dynamic mechanical conditioning and scaffold design into protocols is critical to advancing translational potential for regenerative applications.