766 Keratinocyte differentiation is coupled to mechanical cues through the LINC complex

Abstract

Skin tissue is resilient to mechanical forces, but also can respond to prolonged mechanical forces. For example, tissue expanders are used to generate more skin for breast reconstruction surgery. At the cellular level, multiple mechanical forces are exerted on epidermal keratinocytes. Progenitor keratinocytes, unlike differentiated keratinocytes, have both cell-cell adhesions and cell-extracellular matrix (ECM) adhesions that keep progenitor keratinocytes attached to the basement membrane. During keratinocyte differentiation, progenitor keratinocytes lose cell-ECM adhesions and detach from the basement membrane, but the exact mechanism of how this occurs is not fully understood. External forces must be communicated from the plasma membrane at the outside of the cell to the nucleus, and the Linker of Nucleoskeletal and Cytoskeletal (LINC) complex is poised on the nuclear membrane to sense these mechanical forces. We were interested in determining if there is tension on the LINC complex in keratinocytes and if this tension influences the function of epidermal keratinocytes. Tension on the LINC complex was measured using a FRET-based Nesprin tension sensor, which showed that keratinocytes undergoing differentiation have less tension on the LINC complex compared to progenitor keratinocytes. To investigate the functional consequences of tension on the LINC complex, mice lacking LINC complex components SUN1 and SUN2 proteins were generated. Multiple lines of evidence indicate that Sun1/2 null keratinocytes undergo precocious differentiation both in culture and in vivo. In conclusion, this work demonstrates that mechanical tension on the LINC complex maintains keratinocytes in a progenitor state and identifies tension on the LINC complex as a new regulator of keratinocyte differentiation.