The influence of substrate stiffness gradients on primary human dermal fibroblasts

Hopp, Isabel; Michelmore, Andrew; Smith, Louise E.; Robinson, David; Bachhuka, Akash; Mierczynska, Agnieszka; Vasilev, Krasimir

doi:10.1016/j.biomaterials.2013.03.075

Cited by 93 publications

(67 citation statements)

References 51 publications

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“…The physical cues include gradient stiffness of substrates, gradient pore size and gradient pH value etc. Those cues demonstrated profound influence on cell migration, proliferation, and differentiation [5][6][7][8]. For instance, Jorge et al constructed polyelectrolyte multilayer (PEM) with gradient stiffness by using layer-by-layer assembly technique, which guided the cell adhesion and spreading [9].…”

Section: Introductionmentioning

confidence: 99%

Regulation of the migration of endothelial cells by a gradient density of vascular endothelial growth factor

Cai

2014

Colloids and Surfaces B: Biointerfaces

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Section: Introductionmentioning

confidence: 99%

Regulation of the migration of endothelial cells by a gradient density of vascular endothelial growth factor

Cai

2014

Colloids and Surfaces B: Biointerfaces

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“…Recently, diverse techniques have been utilized for the systematic study of the effects of a substrate's stiffness gradient on cell behaviors. They include diffusion [21], controlled dipping into crosslinking solution [22], microfluidics/photopolymerization [23], gradient mask/photopolymerization [24], convection-alternating flow/photopolymerization [25], photopolymerization using a gradually darkening mask [26], photopolymerization using a sliding mask [16,27], temperature gradients during crosslinking [28], and controlling the height of the substrate [29]. However, the toxicity from residual monomers, precursors, photoinitiators, and crosslinkers [30e33]; different surface chemistry from different densities of crosslinkers along the gradient [22]; relatively narrow ranges of stiffness gradient [29]; and the complexity of fabrication processes are also considered as potential limitations of conventional systems.…”

Section: Introductionmentioning

confidence: 99%

Creating stiffness gradient polyvinyl alcohol hydrogel using a simple gradual freezing–thawing method to investigate stem cell differentiation behaviors

et al. 2015

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“…Dermal fibroblast size can be manipulated in vitro by culture on substrates of varying stiffness (Grinnell & Petroll, 2010; Janmey & Miller, 2011; Hopp et al ., 2013; Buxboim et al ., 2014). Fibroblasts achieve greater size on stiff substrates, compared to more compliant substrates.…”

Section: Introductionmentioning

confidence: 99%

Reduction of fibroblast size/mechanical force down‐regulates TGF ‐β type II receptor: implications for human skin aging

et al. 2015

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SummaryThe structural integrity of human skin is largely dependent on the quality of the dermal extracellular matrix (ECM), which is produced, organized, and maintained by dermal fibroblasts. Normally, fibroblasts attach to the ECM and thereby achieve stretched, elongated morphology. A prominent characteristic of dermal fibroblasts in aged skin is reduced size, with decreased elongation and a more rounded, collapsed morphology. Here, we show that reduced size of fibroblasts in mechanically unrestrained three‐dimensional collagen lattices coincides with reduced mechanical force, measured by atomic force microscopy. Reduced size/mechanical force specifically down‐regulates TGF‐β type II receptor (TβRII) and thus impairs TGF‐β/Smad signaling pathway. Both TβRII mRNA and protein were decreased, resulting in 90% loss of TGF‐β binding to fibroblasts. Down‐regulation of TβRII was associated with significantly decreased phosphorylation, DNA‐binding, and transcriptional activity of its key downstream effector Smad3 and reduced expression of Smad3‐regulated essential ECM components type I collagen, fibronectin, and connective tissue growth factor (CTGF/CCN2). Restoration of TβRII significantly increased TGF‐β induction of Smad3 phosphorylation and stimulated expression of ECM components. Reduced expression of TβRII and ECM components in response to reduced fibroblast size/mechanical force was fully reversed by restoring size/mechanical force. Reduced fibroblast size was associated with reduced expression of TβRII and diminished ECM production, in aged human skin. Taken together, these data reveal a novel mechanism that provides a molecular basis for loss of dermal ECM, with concomitant increased fragility, which is a prominent feature of human skin aging.

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The influence of substrate stiffness gradients on primary human dermal fibroblasts

Cited by 93 publications

References 51 publications

Regulation of the migration of endothelial cells by a gradient density of vascular endothelial growth factor

Regulation of the migration of endothelial cells by a gradient density of vascular endothelial growth factor

Creating stiffness gradient polyvinyl alcohol hydrogel using a simple gradual freezing–thawing method to investigate stem cell differentiation behaviors

Reduction of fibroblast size/mechanical force down‐regulates TGF ‐β type II receptor: implications for human skin aging

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