ECM stiffness primes the TGFβ pathway to promote chondrocyte differentiation

Allen, Jessica L.; Cooke, Margaret E.; Alliston, Tamara

doi:10.1091/mbc.e12-03-0172

Cited by 168 publications

(175 citation statements)

References 78 publications

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“…In addition to playing a role in development, mechanotransduction pathways, activated through microstructural cues and applied mechanical stimulation, can influence stem cell activation and differentiation. Substrate alignment and stiffness can activate canonical RhoA/ROCK1 and FAK pathways to promote MSC differentiation towards musculoskeletal lineages (Allen et al, 2012;Andalib et al, 2013;Kanazawa et al, 2014;Sarasa-Renedo et al, 2006;Xu et al, 2011;Xu et al, 2012). As a result of this increased focus on mechanical cues, bioreactors capable of providing mechanical strain to cell-seeded biomaterials are of particular interest in recent tendon and ligament tissue engineering applications.…”

Section: Introductionmentioning

confidence: 99%

“…Also, recent work by Berthet et al showed that activated Smad 3 binds to the Scleraxis (SCX) and Mohawk (MKX) transcriptional regulators during tendon matrix development (Berthet et al, 2013). Efforts by the Alliston laboratory also reported that crosstalk between mechanical stimuli and growth factor supplementation could activate Smad 1/5/8 as well as drive a feedback loop driven by subsequent endogenous growth factor production to enhance musculoskeletal differentiation (Allen et al, 2012). While the vast majority of those studieshave primarily employed 2D culture environment, new efforts to define linkages between the mechanical microenvironment of the cell, Smad activation and endogenous growth factor production, as well as subsequent stem cell differentiation and tissue development are necessary.…”

Section: Introductionmentioning

confidence: 99%

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Cyclic tensile strain enhances human mesenchymal stem cell Smad 2/3 activation and tenogenic differentiation in anisotropic collagen-glycosaminoglycan scaffolds

Grier

Moy

Harley³

2017

eCM

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Orthopaedic injuries, particularly those involving ligaments and tendons, are some of the most commonly treated ailments in the United States and are associated with both high costs and poor outcomes. Regenerative medicine strategies for tendon injuries could be enhanced by three-dimensional biomaterials that can promote cell alignment and pro-tenogenic differentiation of patientderived MSCs. We have previously described a collagenglycosaminoglycan (CG) scaffold possessing aligned structural features able to promote bone marrow MSC differentiation towards a tenogenic lineage, in the absence of growth factor supplementation. We aimed to employ a bioreactor to enhance MSC tenogenic differentiation within the aligned CG scaffold via cyclic tensile strain (CTS), and further to evaluate the relative effects of strain cycle duration and extended application of repeated cycles of CTS on MSC response. Human MSCs were cultured in CG scaffolds for up to 6 d under static (unloaded) or cyclic tensile strain (1 Hz) for 10 min every 6 h. Time-dependent activation of ERK 1/2 and p38 mechanotransduction pathways was observed within each 6 h strain cycle. MSCs remained viable throughout the experiment and application of CTS robustly upregulated the expression of tendon-specific extracellular matrix proteins and phenotypic markers. Simultaneously, CTS promoted increased phosphorylation of Smad 2/3, suggesting a link between tensile stimulation and TGF-β family growth factor production. Together, we demonstrated the design, fabrication and validation of a high-throughput tensile stimulation bioreactor to increase MSC tenogenic differentiation in porous CG scaffolds.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cyclic tensile strain enhances human mesenchymal stem cell Smad 2/3 activation and tenogenic differentiation in anisotropic collagen-glycosaminoglycan scaffolds

Grier

Moy

Harley³

2017

eCM

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“…During condensation, matrix proteins such as fibronectin, collagen I and the proteoglycan versican are prevalent (Dessau et al, 1980;Kamiya et al, 2006;Kimata et al, 1986;Kulyk et al, 1991). In contrast, matrix deposited by differentiated chondrocytes is rich in collagens II and IX and the proteoglycan aggrecan (Choocheep et al, 2010;Knudson and Knudson, 2001;Knudson and Toole, 1985;Kravis and Upholt, 1985;Kulyk et al, 1991); this matrix might provide the optimal stiffness, which is known to be important for chondrocyte differentiation (Allen et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Fibronectin matrix assembly is essential for cell condensation during chondrogenesis

Singh

Schwarzbauer

2014

Journal of Cell Science

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Mesenchymal cell condensation is the initiating event in endochondral bone formation. Cell condensation is followed by differentiation into chondrocytes, which is accompanied by induction of chondrogenic gene expression. Gene mutations involved in chondrogenesis cause chondrodysplasias and other skeletal defects. Using mesenchymal stem cells (MSCs) in an in vitro chondrogenesis assay, we found that knockdown of the diastrophic dysplasia (DTD) sulfate transporter (DTDST, also known as SLC26A2), which is required for normal cartilage development, blocked cell condensation and caused a significant reduction in fibronectin matrix. Knockdown of fibronectin with small interfering RNAs (siRNAs) also blocked condensation. Fibrillar fibronectin matrix was detected prior to cell condensation, and its levels increased during and after condensation. Inhibition of fibronectin matrix assembly by use of the functional upstream domain (FUD) of adhesin F1 from Streptococcus pyogenes prevented cell condensation by MSCs and also by the chondrogenic cell line ATDC5. Our data show that cell condensation and induction of chondrogenesis depend on fibronectin matrix assembly and DTDST, and indicate that this transporter is required earlier in chondrogenesis than previously appreciated. They also raise the possibility that certain of the skeletal defects in DTD patients might derive from the link between DTDST, fibronectin matrix and condensation.

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“…Passive mechanical inputs include physical properties such as substrate stiffness, ECM alignment, and adhesive affinity..etc. The static physical property of the microenvironment can have a profound impact on cell physiology, producing active biological outputs in cytoskeleton remodeling, gene expression, changes in membrane trafficking, altered signaling, and stem cell differentiation (4)(5)(6)(7)(8)(9). Active inputs, on the other hand, encompass externally applied forces, such as cell stretching and fluid shear stress.…”

Section: Active Modes Of Mechanotransductionmentioning

confidence: 99%

Biophysical Tools for Cellular and Subcellular Mechanical Actuation of Cell Signaling

Liu

2016

Biophysical Journal

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The ability to spatially control cell signaling can help resolve fundamental biological questions. Optogenetic and chemical dimerization techniques along with fluorescent biosensors to report cell signaling activities have enabled researchers to both visualize and perturb biochemistry in living cells. A number of approaches based on mechanical actuation using forcefield gradients have emerged as complementary technologies to manipulate cell signaling in real time. This review covers several technologies, including optical, magnetic, and acoustic control of cell signaling and behavior and highlights some studies that have led to novel insights. I will also discuss some future direction on repurposing mechanosensitive channel for mechanical actuation of spatial cell signaling.

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ECM stiffness primes the TGFβ pathway to promote chondrocyte differentiation

Cited by 168 publications

References 78 publications

Cyclic tensile strain enhances human mesenchymal stem cell Smad 2/3 activation and tenogenic differentiation in anisotropic collagen-glycosaminoglycan scaffolds

Cyclic tensile strain enhances human mesenchymal stem cell Smad 2/3 activation and tenogenic differentiation in anisotropic collagen-glycosaminoglycan scaffolds

Fibronectin matrix assembly is essential for cell condensation during chondrogenesis

Biophysical Tools for Cellular and Subcellular Mechanical Actuation of Cell Signaling

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