Extracellular Matrix Stiffness and Composition Regulate the Myofibroblast Differentiation of Vaginal Fibroblasts

Abstract

<jats:p>Fibroblast to myofibroblast differentiation is a key feature of wound-healing in soft tissues, including the vagina. Vaginal fibroblasts maintain the integrity of the vaginal wall tissues, essential to keep pelvic organs in place and avoid pelvic organ prolapse (POP). The micro-environment of vaginal tissues in POP patients is stiffer and has different extracellular matrix (ECM) composition than healthy vaginal tissues. In this study, we employed a series of matrices with known stiffnesses, as well as vaginal ECMs, in combination with vaginal fibroblasts from POP and healthy tissues to investigate how matrix stiffness and composition regulate myofibroblast differentiation in vaginal fibroblasts. Stiffness was positively correlated to production of α-smooth muscle actin (α-SMA). Vaginal ECMs induced myofibroblast differentiation as both α-SMA and collagen gene expressions were increased. This differentiation was more pronounced in cells seeded on POP-ECMs that were stiffer than those derived from healthy tissues and had higher collagen and elastin protein content. We showed that stiffness and ECM content regulate vaginal myofibroblast differentiation. We provide preliminary evidence that vaginal fibroblasts might recognize POP-ECMs as scar tissues that need to be remodeled. This is fundamentally important for tissue repair, and provides a rational basis for POP disease modelling and therapeutic innovations in vaginal reconstruction.</jats:p>

Substrate stiffness engineered to replicate disease conditions influence senescence and fibrotic responses in primary lung fibroblasts

“…Higher proliferation, contractility and activation of fibroblasts are all reported as responses to a stiffer environment (42-44). In this regard, the proliferation and high viability of fibroblasts grown on both soft and stiff hydrogels observed in this study were comparable to observations from previous investigations (43, 45, 46). Furthermore, the morphology of fibroblasts on soft gels was comparable to fibroblasts on stiff gels.…”

Role of Fibroblasts and Myofibroblasts on the Pathogenesis and Treatment of Pelvic Organ Prolapse

“…Differentiation of fibroblasts to myofibroblasts as evidenced by the increase in α-SMA and collagen gene expression was more pronounced in cells seeded on POP-ECMs which were stiffer than ECMs derived from healthy tissues. It was concluded that when vaginal fibroblasts are seeded on prolapsed ECM, they differentiate into myofibroblast as they recognize surfaces as granulation tissues that need to be remodeled [ 77 ]. Prolonged exposure of vaginal fibroblasts to an abnormal prolapsed matrix results in phenotypical changes.…”

Mechanobiological Implications of Cancer Progression in Space

“…The expression of α-SMA depends on the concentration of TGF-β1, and is usually abundant in fibroblasts near a scar to assist in scar contraction ( Huang et al, 2001 ; Shinde et al, 2017 ). The contractile protein α-SMA induces transdifferentiation of fibroblasts into myofibroblast, which excrete ECM compounds such as collagen I and III, as well as play a key role in wound closure and ECM contraction ( Ruiz-Zapata et al, 2020 ). Myofibroblasts, also known as contractile cell, increase ECM rigidity by enhancing integrin binding, and cause tissue fibrosis in severe cases ( Klingberg et al, 2013 ).…”