Matrix stiffness mechanosensing modulates the expression and distribution of transcription factors in Schwann cells

Abstract

After peripheral nerve injury, mature Schwann cells (SCs) de‐differentiate and undergo cell reprogramming to convert into a specialized cell repair phenotype that promotes nerve regeneration. Reprogramming of SCs into the repair phenotype is tightly controlled at the genome level and includes downregulation of pro‐myelinating genes and activation of nerve repair‐associated genes. Nerve injuries induce not only biochemical but also mechanical changes in the tissue architecture which impact SCs. Recently, we showed that SCs mechanically sense the stiffness of the extracellular matrix and that SC mechanosensitivity modulates their morphology and migratory behavior. Here, we explore the expression levels of key transcription factors and myelin‐associated genes in SCs, and the outgrowth of primary dorsal root ganglion (DRG) neurites, in response to changes in the stiffness of generated matrices. The selected stiffness range matches the physiological conditions of both utilized cell types as determined in our previous investigations. We find that stiffer matrices induce upregulation of the expression of transcription factors Sox2, Oct6, and Krox20, and concomitantly reduce the expression of the repair‐associated transcription factor c‐Jun, suggesting a link between SC substrate mechanosensing and gene expression regulation. Likewise, DRG neurite outgrowth correlates with substrate stiffness. The remarkable intrinsic physiological plasticity of SCs, and the mechanosensitivity of SCs and neurites, may be exploited in the design of bioengineered scaffolds that promote nerve regeneration upon injury.

Pin1/YAP pathway mediates matrix stiffness‐induced epithelial–mesenchymal transition driving cervical cancer metastasis via a non‐Hippo mechanism

“…YAP is widely present in vivo and functions as a sensor and mediator of mechanical signals indicative of the cellular microenvironment. 28 As a typical mechanism of YAP regulation, the phosphorylation cascade reaction of the Hippo pathway has been identified. 29 The Hippo pathway phosphorylates YAP through large tumor suppressor (LATS), causing it to stay in the cytoplasm to inhibit its activity, while dephosphorylated YAP enters the nucleus with the transcriptional enhancer subdomain (TEAD), regulating the transcription of specific genes thereby promoting cell proliferation and survival.…”

Substrate stiffness in nerve cells

“…Stiffer substrates (30 kPa compared to 1.5 kPa) promote Schwann cell differentiation and prevent Schwann cell dedifferentiation, with increased expression of pro-myelin proteins, Mbp myelin protein [40, 41], and Krox 20 pro-myelin protein [42] and decreased expression of the dedifferentiation marker c-Jun. With increasing substrate stiffness, the migration distance of Schwann progenitor cells from the axon increases [23] as does actin skeleton traction [43].…”

Development and In Vitro Differentiation of Schwann Cells

“…For example, mechanical stimuli and culture substrates regulate YAP/TAZ signaling in Schwann cells, which is also involved in differentiation processes [ 188 , 190 , 191 ]. In rat Schwann cells, YAP/TAZ activation through mechanotransduction acts synergistically with laminin to induce upregulation of myelin-associated factors [ 191 , 366 , 380 ]. Hence, it would be interesting to also explore such mechanisms in the differentiation of human Schwann cells in vitro.…”