Tissue fibrosis regulates the senescent fate of Schwann cells through piezo1-dependent mechanotransduction (PRJCA017532)

Following peripheral nerve injury, long-term repair of the injury site is accompanied by a gradual increase in collagen fibres and the formation of localized scar tissue. Excessive nerve scar tissue is harmful to the nerve repair. Here we show that scar formation after nerve injury leads to changes in the local physical microenvironment, specifically increased stiffness in the physical environment of the cells, which can lead to senescence of the Schwann cells. Senescent Schwann cells acquire a senescence-associated secretory phenotype and a reduced capacity for nerve repair. Mechanistically, the physical environment affects the opening of mechanosensitive calcium channels, triggering calcium inward flow and leading to the expression of senescence-associated genes. Simultaneous activation of piezo1 also leads to activation of the TGF pathway, further enhancing fibrotic gene expression and creating a positive feedback loop associated with senescence. The use of piezo1 inhibition and GSMTX4 reduces cellular senescence. Thus, scar fibrosis activates piezo1 in Schwann cells and triggers cellular senescence.