Decreased Substrate Stiffness Promotes a Hypofibrotic Phenotype in Cardiac Fibroblasts

Childers, Rachel C.; Lucchesi, Pamela A.; Gooch, Keith J.

doi:10.3390/ijms22126231

Cited by 10 publications

(8 citation statements)

References 45 publications

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“…We speculated that this structural compromise led to a significant decrease in the stiffness of the scaffold, while fibroblasts tend to differentiate into a hypofibrotic phenotype on a soft substrate. [53] These results indicated that the nanomicro topology of P6 and P6-RS activated the mechanotransduction pathway of cells grown in a static environment. Nevertheless, the cobweb-inspired structures P6 and P6-RS inhibited fibrosis in a dynamic environment owing to their unique mechanical properties.…”

Section: In Vitro Gene Expression Analysismentioning

confidence: 73%

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Cobweb‐Inspired Micro/Nanostructured Scaffolds for Soft Tissue Regeneration with Inhibition Effect of Fibrosis under Dynamic Environment

Jiao,

Li,

Liu

et al. 2023

Adv Healthcare Materials

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In soft tissue repair, fibrosis can lead to repair failure and long‐term chronic pain in patients. Excessive mechanical stimulation of fibroblasts is one of the causes of fibrosis during abdominal wall regeneration. Inspired by the cobweb, a polycaprolactone beaded fiber is prepared by electrospinning. The cobweb‐inspired structure attenuates the mechanical stimulation of cells under a dynamic environment. Nano‐protrusions are introduced into the scaffold for further inhibition of fibrosis by self‐induced crystallization. A machine is built for in vitro dynamic culture and rat abdominal subcutaneous embedding experiments are performed to verify the inhibiting effect of fibrosis in a dynamic environment in vivo. Results show that the expression of integrin β1 and α‐smooth muscle actin is inhibited by the cobweb‐inspired structure under dynamic culture. The results of hematoxylin and eosin and Masson's trichrome indicate that the cobweb‐inspired structure has a good inhibitory effect on fibrosis in a dynamic environment in vivo. In general, the cobweb‐inspired scaffold with nano‐protrusions has a good ability to inhibit fibrosis under both static and dynamic environments. It is believed that the scaffold has promising applications in the field of inhibiting fibrosis caused by mechanical stimulation.

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Section: In Vitro Gene Expression Analysismentioning

confidence: 73%

Section: Resultsmentioning

confidence: 99%

Cobweb‐Inspired Micro/Nanostructured Scaffolds for Soft Tissue Regeneration with Inhibition Effect of Fibrosis under Dynamic Environment

Jiao,

Li,

Liu

et al. 2023

Adv Healthcare Materials

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“…The mRNA expression of connective tissue growth factor increased with cell substrate stiffness. In this case, the rat fibroblasts were derived from hearts subjected to sham or aortocaval fistula surgery [ 25 ]. In contrast, human lung fibroblasts cultured on stiff matrix (20 kPa) demonstrated elevated fibronectin 1 and Col1A1 gene expression [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

The Stiffness of Cardiac Fibroblast Substrates Exerts a Regulatory Influence on Collagen Metabolism via α2β1 Integrin, FAK and Src Kinases

Gałdyszyńska

Radwańska

Szymański

et al. 2021

Cells

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Information about mechanical strain in the extracellular space is conducted along collagen fibers connected with integrins and then transmitted within cells. An aim of the study is to verify the hypothesis that the stiffness of cardiac human fibroblast substrates exerts a regulatory effect on collagen metabolism via integrin α2β1 and downstream signaling. The experiments were performed on human cardiac fibroblasts cultured on stiff or soft polyacrylamide gels. Extracellular and intracellular collagen content, metalloproteinase-1 (MMP-1), metalloproteinase-9 (MMP-9) and expression of the α1 chain of the procollagen type I gene (Col1A1) were elevated in cultures settled on soft substrate. The substrate stiffness did not modify tissue inhibitors of matrix metalloproteinase capacity (TIMPs 1–4). Integrin α2β1 inhibition (TC-I 15) or α2 subunit silencing resulted in augmentation of collagen content within the culture. Expression of Col1A1 and Col3A1 genes was increased in TC-I 15-treated fibroblasts. Total and phosphorylated levels of both FAK and Src kinases were elevated in fibroblasts cultured on stiff substrate. Inhibition of FAK (FAK kinase inhibitor 14) or Src kinase (AZM 47527) increased collagen content within the culture. The substrate stiffness exerted a regulatory influence on collagen metabolism via integrin α2β1 and its downstream signaling (FAK and Src kinases) in cardiac fibroblasts.

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“…Fibroblast expanded in stiff microenvironments maintain a profibrotic phenotype over several weeks when switched to a soft substrate. Conversely, soft substrate culture upregulates MMP-1, MMP-3 and MMP-13 production and reduces expression of fibrosis-associated genes (such as α-SMA, Col type-1, and CTGF) in skin or cardiac fibroblasts, restraining their activation when plated on a stiff culture substrate [ 41 , 42 ]. After myocardial infarction, the mechanical properties of the heart change regionally and over time, inducing distinct phenotypes in cardiac fibroblasts that can be recapitulated in vitro [ 43 ].…”

Section: Mechanical Memorymentioning

confidence: 99%

Fibroblast Memory in Development, Homeostasis and Disease

Kirk

Ahmed

Rognoni

2021

Cells

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Fibroblasts are the major cell population in the connective tissue of most organs, where they are essential for their structural integrity. They are best known for their role in remodelling the extracellular matrix, however more recently they have been recognised as a functionally highly diverse cell population that constantly responds and adapts to their environment. Biological memory is the process of a sustained altered cellular state and functions in response to a transient or persistent environmental stimulus. While it is well established that fibroblasts retain a memory of their anatomical location, how other environmental stimuli influence fibroblast behaviour and function is less clear. The ability of fibroblasts to respond and memorise different environmental stimuli is essential for tissue development and homeostasis and may become dysregulated in chronic disease conditions such as fibrosis and cancer. Here we summarise the four emerging key areas of fibroblast adaptation: positional, mechanical, inflammatory, and metabolic memory and highlight the underlying mechanisms and their implications in tissue homeostasis and disease.

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Decreased Substrate Stiffness Promotes a Hypofibrotic Phenotype in Cardiac Fibroblasts

Cited by 10 publications

References 45 publications

Cobweb‐Inspired Micro/Nanostructured Scaffolds for Soft Tissue Regeneration with Inhibition Effect of Fibrosis under Dynamic Environment

Cobweb‐Inspired Micro/Nanostructured Scaffolds for Soft Tissue Regeneration with Inhibition Effect of Fibrosis under Dynamic Environment

The Stiffness of Cardiac Fibroblast Substrates Exerts a Regulatory Influence on Collagen Metabolism via α2β1 Integrin, FAK and Src Kinases

Fibroblast Memory in Development, Homeostasis and Disease

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