Rapid cyclic stretching of cultured human visceral smooth muscle cells promotes a synthetic, proinflammatory phenotype

TL;DR

Stretching bowel smooth muscle cells rapidly changes their behavior to become proinflammatory, which could contribute to bowel diseases.

Contribution

Demonstrates that high-frequency mechanical stress rapidly induces a synthetic, proinflammatory phenotype in human intestinal smooth muscle cells.

Findings

High-frequency cyclic stretching alters gene expression in smooth muscle cells, promoting a synthetic and proinflammatory state.

Loaded cells show increased expression of cytokines and altered axon guidance molecules and growth factors.

Mechanical stress may convert contractile smooth muscle cells into fibroblast-like or proinflammatory cells.

Abstract

Bowel smooth muscle experiences mechanical stress constantly during normal function and pathologic mechanical stressors in disease states. We tested the hypothesis that pathologic mechanical stress could alter transcription to induce smooth muscle phenotypic class switching. To test this hypothesis, primary human intestinal smooth muscle cells (HISMCs), seeded on electrospun aligned poly-ε-caprolactone nano-fibrous scaffolds, were subjected to pathologic, high-frequency (1 Hz) uniaxial 3% cyclic stretch (loaded) or kept unloaded in culture for 6 hours. RNA-Seq, quantitative PCR (qPCR), and quantitative IHC defined loading-induced changes in gene expression. NicheNet predicted how differentially expressed genes might affect HISMCs and other bowel cells. These studies show loading induced differential expression of 4,537 HISMC genes. Loaded HISMCs had a less contractile phenotype, with increased expression of synthetic SMC genes, proinflammatory cytokines, and altered expression of axon guidance molecules, growth factors, and morphogens. Many differentially expressed genes encode secreted ligands that could act cell autonomously on smooth muscle and on other cells in the bowel wall. These data show that HISMCs undergo remarkably rapid phenotypic plasticity in response to mechanical stress that may convert contractile HISMCs into proliferative fibroblast-like cells or proinflammatory cells. These mechanical stress–induced changes in HISMC gene expression may be relevant for human bowel disease.

Cyclically stretching bowel smooth muscle cells at a much higher frequency than what the bowel normally experiences induces a proinflammatory state in these cells.

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