Nuclear mechanotransduction and genome regulation during cellular ageing, reprogramming and rejuvenation
Cellular ageing result in major alterations in nuclear mechanotransduction pathways and genome programs. However, the cytoskeletal remodelling mechanisms facilitating the activation of nuclear mechanotransduction pathways and how the 3D chromatin architecture regulates such cell-state transitions are still unclear. In recent work, we discovered novel mechano-genomic routes to control fibroblast cell-state transitions, leading to their stem-ness and rejuvenation. In future work, we will first identify potential mechano-genomic biomarkers characterizing the differences between young, adult and old human dermal fibroblasts. We will then implement mechanical routes to induce partial reprogramming of the older human dermal fibroblasts and their subsequent re-differentiation to rejuvenated (younger) fibroblast cell states. Using single-cell correlative imaging and chromosome accessibility assays combined with whole genome transcriptomics, we will study the mechanisms underlying fibroblast reprogramming and the mechanical check-points in cell-fate decisions during their re-differentiation in tissue organoids. Further, we will implant such patient specific rejuvenated human dermal fibroblasts into aged ex vivo human skin biopsies to study whether this could provide robust tissue regeneration models for clinical applications.