Collagen-binding integrins play a crucial role in facilitating fibroblast-collagen interactions and regulating cellular functions. In this study, we identified that among four collagen-binding integrins, integrin ��11 (��11) as the predominant integrin in human skin dermal fibroblasts, and loss ��11 expression contributes to skin dermal aging. ��11��1 is critical for regulating fibroblast-collagen interactions, including cell adhesion, spreading, morphology, mechanical tension, and the production of collagenous extracellular matrix (ECM). Transforming growth factor-beta (TGF-��) is recognized as the primary regulator of ��11 expression. Notably, dermal fibroblasts in aged human skin demonstrate impaired TGF-�� signaling, which coincides with a loss of ��11 expression, while the expression of other collagen-binding integrins remains unchanged. Similarly, in senescent dermal fibroblasts in vitro, impaired TGF-�� signaling is associated with a significant reduction in ��11 expression, whereas other collagen-binding integrins are upregulated or unaffected. Furthermore, collapsed dermal fibroblasts, a key characteristic of dermal fibroblasts in aged human skin, specifically downregulate ��11, while other collagen-binding integrins are upregulated or remain unchanged. These findings suggest a negative feedback loop in which an impaired TGF-��- ��11��1 axis and fibroblast collapse promote dermal aging in human skin. This self-reinforcing cycle reflects the progressive and unidirectional nature of biological aging.
