Abstract
Previously, we reported that the conformational transition of collagen I matrix plays, along with differentiation stimuli, a regulatory role in determination of differentiation lineage of bone marrow stromal sells via distinct signaling pathways specific for the structural state of the matrix. The present study addresses mechanisms underlying differential structural conformation-specific effects of collagen matrices on differentiation into diverse lineages. The results obtained suggest that the pivotal player in the observed matrix conformation-mediated regulation is a differential cellular stress response elicited by the exposure to native but not to denatured collagen I matrix. The stress causing such a response appears to be generated by matrix contraction and mediated by Alpha2Beta1 integrins engaged on native but not on denatured collagen I matrix. The principal facet of the observed phenomenon is not the nature of a stress but general stress response: when cells on denatured collagen I matrix are subjected to thermal stress, osteogenic pathway shifts to that seen on native collagen I matrix. Importantly, cellular stress response might be commonly involved in determination of differentiation lineage. Indeed, distinct components of cellular stress response machinery appear to regulate differentiation into diverse lineages. Thus, augmentation of Hsp90 levels enables the operation of efficient Alpha1Beta1/Alpha2Beta1 integrin-driven ERK activation pathways hence facilitating osteogenesis and suppressing adipogenesis, whereas myogenesis of satellite stem cells appears to be promoted by native collagen I matrix-elicited activation and nuclear translocation of another stress response component, Beta-catenin, shown to be essential for skeletal myogenesis, and chondrogenesis may involve stress-mediated elevation of yet another stress response constituent, Hsp70, shown to be an interactive partner of the chondrogenic transcription factor SOX9. The proposed concept of the integral role of cellular stress response in tissue generation and maintenance suggests new therapeutic approaches and indicates novel tissue engineering strategies.