Myofibroblast Differentiation Of Fetal Fibroblasts Is Inhibited In Response To Ecm Rigidity And Tgf-b1
Aron Parekh, PhD, Rachel J. Jerrell, Mitchell J. Leih.
Vanderbilt University Medical Center, Nashville, TN, USA.
During dermal wound healing, fibroblasts differentiate into myofibroblasts and excessively contract and remodel newly deposited extracellular matrix (ECM) leading to scarring. Myofibroblast differentiation is driven by biomechanical factors in the wound environment including ECM rigidity and transforming growth factor-b1 (TGF-b1). These environmental factors promote the formation of mature focal adhesions and stress fibers rich in a-smooth muscle actin (a-SMA) that generate the large contractile forces necessary for wound closure. In contrast, fibroblasts orchestrate scarless healing of fetal dermal wounds with minimal myofibroblast involvement or contraction suggesting that smaller cellular forces contribute to this process. However, it remains unclear whether this regenerative response is a result of unique biomechanical characteristics of fetal fibroblasts or their wound environment which lacks TGF-b1 and is composed of a more compliant ECM than found in adult wounds. Therefore, we tested whether physiologic rigidities and TGF-b1 promote actomyosin contractility and myofibroblast differentiation in fetal fibroblasts using a fibronectin-polyacrylamide gel (PAA) system that spanned the mechanical properties reported for different wound healing stages. We found that focal adhesion formation and/or maturation was impaired in fetal fibroblasts at early and late time points on rigid PAAs that mimicked late-stage granulation tissue when compared to adult fibroblasts. These differences coincided with less traction force generation by fetal versus adult fibroblasts on these PAAs. Furthermore, TGF-b1 did not induce myofibroblast differentiation of fetal fibroblasts on rigid PAAs in comparison to adult fibroblasts which exhibited increased focal adhesion formation and maturation, a-SMA levels, and traction forces. Overall, our data suggest that fetal fibroblasts have inherently different biomechanical responses to environmental factors resulting in a unique contractile phenotype that may prevent myofibroblast differentiation.
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