Compressive forces induce epigenetic activation of aged human dermal fibroblasts through ERK signaling pathway

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Abstract Age-related changes in human dermal fibroblasts (HDFs) contribute to impaired wound healing and skin aging. While these changes result in altered mechanotransduction, the epigenetic basis of rejuvenating aging cells remains a significant challenge. This study investigates the effects of compressive forces on nuclear mechanotransduction and epigenetic rejuvenation in aged HDFs. Using a compressive force application model, the activation of HDFs through alpha-smooth muscle actin (ɑ-SMA) is demonstrated. Sustained compressive forces induce significant epigenetic modifications, including chromatin remodeling and altered histone methylation patterns. These epigenetic changes correlate with enhanced cellular migration and rejuvenation. Small-scale drug screening identifies the extracellular signal-regulated kinase (ERK) signaling pathway as a key mediator of compression-induced epigenetic activation. Furthermore, implanting aged cell spheroids to an aged skin model and subjecting the tissue with compressing forces resulted in increased collagen I protein levels. Collectively, these findings demonstrate that applying compressive force to aged fibroblasts activates global epigenetic changes through the ERK signaling pathway, ultimately rejuvenating cellular functions with potential applications for wound healing and skin tissue regeneration. Significance Statement Partial rejuvenation of aging cells is desirable but is still a major challenge. In this paper, we demonstrate that aged human dermal fibroblasts, embedded in a 3D collagen hydrogel matrix as spheroids, subjected to external static compressive force exhibit partial rejuvenation. Through immunofluorescence, small-scale inhibitor screen and gene expression analysis, we identify some of the critical mechanotransduction pathways in this process. Collectively, our results provide compelling evidence that tissue compression results in the activation of potential rejuvenation pathways in aging cells.

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