Tissue Stiffness Dictates Development, Homeostasis, and Disease Progression

Handorf, Andrew M.; Yun, Zhou; Halanski, Matthew A.; Li, Wan‐Ju

doi:10.1080/15476278.2015.1019687

Cited by 484 publications

(417 citation statements)

References 100 publications

(102 reference statements)

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“…We quantified cell area ( Figure 2e) and LAP is an efficient photoinitiator to synthesize 2D PEG-PC hydrogels in a 96-well plate format. In addition to protein composition, [30][31] every tissue has a specific stiffness range [32][33] that can be mimicked using hydrogels. We had developed a 2D PEG-PC hydrogel that is polymerized with Irgacure 2959 (Irgacure), 34 a commonly used photoinitiator in hydrogel synthesis.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Complementary, Semiautomated Methods for Creating Multidimensional PEG-Based Biomaterials

Brooks

Jansen

Gencoglu

et al. 2018

ACS Biomater. Sci. Eng.

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Tunable biomaterials that mimic selected features of the extracellular matrix (ECM), such as its stiffness, protein composition, and dimensionality, are increasingly popular for studying how cells sense and respond to ECM cues. In the field, there exists a significant trade-off for how complex and how well these biomaterials represent the in vivo microenvironment, versus how easy they are to make and how adaptable they are to automated fabrication techniques. To address this need to integrate more complex biomaterials design with high-throughput screening approaches, we present several methods to fabricate synthetic biomaterials in 96-well plates and demonstrate that they can be adapted to semiautomated liquid handling robotics. These platforms include 1) glass bottom plates with covalently attached ECM proteins, and 2) hydrogels with tunable stiffness and protein composition with either cells seeded on the surface, or 3) laden within the three-dimensional hydrogel matrix. This study includes proof-of-concept results demonstrating control over breast cancer cell line phenotypes via these ECM cues in a semi-automated fashion. We foresee the use of these methods as a mechanism to bridge the gap between high-throughput cell-matrix screening and engineered ECM-mimicking biomaterials.

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Section: Resultsmentioning

confidence: 99%

“…[33][34] Also, the silane treatment allowed for the long-term adherence of the hydrogels to the well surface (Figure 3b). Both MDA-MB-231…”

Section: Discussionmentioning

confidence: 99%

Complementary, Semiautomated Methods for Creating Multidimensional PEG-Based Biomaterials

Brooks

Jansen

Gencoglu

et al. 2018

ACS Biomater. Sci. Eng.

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show abstract

“…On the one hand, cells are able to synthesize, breakdown, or otherwise rearrange ECM components to change ECM composition and topography. On the other hand, the biophysical properties of the ECM also play a role in directing cell functions and, thus, any changes in ECM dynamics will influence adjacent cells and their cellular activities [26,27]. By maintaining the feedback loop between cells and their ECM, tissues/cells can readily adapt to the physical forces imposed on them [26,28].…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, the biophysical properties of the ECM also play a role in directing cell functions and, thus, any changes in ECM dynamics will influence adjacent cells and their cellular activities [26,27]. By maintaining the feedback loop between cells and their ECM, tissues/cells can readily adapt to the physical forces imposed on them [26,28]. However, when the tissue homeostasis becomes imbalanced, tissue function generally becomes impaired as a result of aberrant cellular behavior [29].…”

Section: Discussionmentioning

confidence: 99%

Extracellular Matrix Elasticity Regulates Osteocyte Gap Junction Elongation: Involvement of Paxillin in Intracellular Signal Transduction

Zhang

Zhou

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Osteocytes can sense and respond to extracellular stimuli, including biochemical factors throughout the cell body, dendritic processes, and cilia bending. However, further exploration is required of osteocyte function in response to substrate stiffness, an important passive mechanical cue at the interface between osteocytes and the extracellular matrix, and the deep bio-mechanism in osteocytes involving mechanosensing of cell behavior. Methods: We fabricated silicon-based elastomer polydimethylsiloxane substrates with different stiffnesses but with the same surface topologies. We then seeded osteocytes onto the substrates to examine their responses. Methodologies used included scanning electron microscopy (SEM) for cell morphology, confocal laser scanning microscopy (CLSM) for protein distribution, western blot for protein levels, co-immunoprecipitation for protein interactions, and quantitative real-time polymerase chain reaction for gene expression. Results: SEM images revealed that substrate stiffness induced a change in osteocyte morphology, and CLSM of F-actin staining revealed that substrate stiffness can alter the cytoskeleton. These results were accompanied by changes in focal adhesion capacity in osteocytes, determined via characterization of vinculin expression and distribution. Furthermore, on the exterior of the cell membrane, fibronectin was altered by substrate stiffness. The fibronectin then induced a change in paxillin on the inner membrane of the cell via protein–protein interaction through transmembrane processing. Paxillin led to changes in connexin 43 via protein–protein binding, thereby influencing osteocyte gap junction elongation. Conclusion: This process -from mechanosensing and mechanotransduction to cell function - not only indicates that the effects of mechanical factors on osteocytes can be directly sensed from the cell body, but also indicates the involvement of paxillin transduction.

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“…An alternative approach for blocking integrin function in fibrosis would be to somehow perturb downstream signaling events arising from integrin activation that perpetuate fibrosis. One example of this approach would be to target collagen cross-linking as this process increases local tissue stiffness; stiffer collagen induces further integrin activation and clustering, which maintains the fibrotic activation loop (Handorf et al 2015;Levental et al 2009;Lopez et al 2008). …”

Section: Targeting Collagen Adhesion Receptors In Anti-fibrotic Theramentioning

confidence: 99%

Contribution of collagen adhesion receptors to tissue fibrosis

Coelho

McCulloch

2016

Cell Tissue Res

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Fibrosis is the result of a wound-healing response that fails to restore normal tissue structure function. One of the critical hallmarks of fibrosis is disrupted collagen remodeling. In tissue homeostasis, the production, deposition and organization of collagen is balanced by the degradation and remodeling of collagen within the existing matrix. After injury or chronic infection, tissues initiate a wound-healing response that is intended to create a new ECM for restoring tissue structure and function. If the wound-healing response is dysregulated or if the tissue injury or infection is severe or long-lasting, collagen deposition exceeds collagen degradation and the tissue repair process leads to fibrosis. The fibrotic repair response is extraordinarily complex and involves a wide spectrum of cells, signaling pathways and regulatory systems, some of which can be readily disrupted and thereby contribute to fibrotic lesions. The dysregulated collagen remodeling is a common end-point of all fibrotic disorders, and one of the rate-limiting steps of collagen remodeling is the binding of cells to collagen fibrils by specific cell adhesion receptors. In this review, we describe how the expression and function of collagen adhesion receptors contribute to collagen processing events that contribute to tissue fibrosis. Graphical abstract Balance between collagen remodeling in health and disease.

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Tissue Stiffness Dictates Development, Homeostasis, and Disease Progression

Cited by 484 publications

References 100 publications

Complementary, Semiautomated Methods for Creating Multidimensional PEG-Based Biomaterials

Complementary, Semiautomated Methods for Creating Multidimensional PEG-Based Biomaterials

Extracellular Matrix Elasticity Regulates Osteocyte Gap Junction Elongation: Involvement of Paxillin in Intracellular Signal Transduction

Contribution of collagen adhesion receptors to tissue fibrosis

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