Integrin Signaling and ECM Proteins in hPSC Maintenance and Differentiation

Integrin signaling serves as a fundamental regulator in human pluripotent stem cell (hPSC) biology, mediating adhesion, survival, and pluripotency through interactions with extracellular matrix (ECM) components. Specific integrins, including α6β1, αvβ5, and α3β1, engage ECM ligands such as laminin-511/521 and vitronectin (VTN) to sustain hPSC self-renewal. These engagements trigger essential downstream pathways, including PI3K/AKT, MAPK/ERK, focal adhesion kinase (FAK)-Src, and RhoA/Rho-associated protein kinase (ROCK), thereby maintaining the expression of pluripotency factors like OCT4, NANOG, and SOX2 while integrating mechanotransductive cues. FAK and Src convert ECM-derived mechanical signals into biochemical responses, regulating cytoskeletal reorganization, YAP/TAZ nuclear translocation, and context-dependent gene expression. For scalable, xeno-free culture, recombinant substrates such as truncated vitronectin (VTN-N) and laminin-511/521 E8 fragments, paired with defined media (e.g., Essential 8 or mTeSR1), support robust hPSC expansion under good manufacturing practice (GMP) conditions. Extending to differentiation, integrin-ECM crosstalk directs lineage commitment across diverse fates, including hematopoietic, cardiovascular, neural, hepatic, epithelial, endodermal, and oligodendroglial lineages, by fine-tuning signaling specificity and ECM composition. This review focuses on recent advances in the mechanistic interplay between integrin signaling and ECM proteins in hPSC maintenance, mechanotransduction, and lineage-directed differentiation, emphasizing defined culture systems and their translational potential in regenerative medicine.