Cell force-mediated matrix reorganization underlies multicellular network assembly

Davidson, Christopher D.; Wang, William Y.; Zaimi, Ina; Jayco, Danica Kristen P.; Baker, Brendon M.

doi:10.1038/s41598-018-37044-1

Cited by 78 publications

(90 citation statements)

References 59 publications

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“…When ROCK is inhibited, MLCK may still be capable of inducing sufficient contraction of the hydrogel to counteract the Y27632‐mediated inhibition. A recent study showed that when HUVECs grown on hydrogel matrices were treated with Y27632 and blebbistatin, the cells tended to adhere more to the matrix and led to reduced interaction between neighboring cells, and thus less networks formed (Davidson, Wang, Zaimi, Jayco, & Baker, ). All this suggests that cell‐mediated contractile forces are important for vascular network formation.…”

Section: Discussionmentioning

confidence: 99%

ECM concentration and cell‐mediated traction forces play a role in vascular network assembly in 3D bioprinted tissue

Zhang

Varkey

Zhan

et al. 2020

Biotech & Bioengineering

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Tissue vascularization is critical to enable oxygen and nutrient supply. Therefore, establishing expedient vasculature is necessary for the survival of tissue after transplantation. The use of biomechanical forces, such as cell‐induced traction forces, may be a promising method to encourage growth of the vascular network. Three‐dimensional (3D) bioprinting, which offers unprecedented versatility through precise control over spatial distribution and structure of tissue constructs, can be used to generate capillary‐like structures in vitro that would mimic microvessels. This study aimed to develop an in vitro, 3D bioprinted tissue model to study the effect of cellular forces on the spatial organization of vascular structures and tissue maturation. The developed in vitro model consists of a 3D bioprinted polycaprolactone (PCL) frame with a gelatin spacer hydrogel layer and a gelatin–fibrin–hyaluronic acid hydrogel layer containing normal human dermal fibroblasts and human umbilical vein endothelial cells printed as vessel lines on top. The formation of vessel‐like networks and vessel lumens in the 3D bioprinted in vitro model was assessed at different fibrinogen concentrations with and without inhibitors of cell‐mediated traction forces. Constructs containing 5 mg/ml fibrinogen had longer vessels compared to the other concentrations of fibrinogen used. Also, for all concentrations of fibrinogen used, most of the vessel‐like structures grew parallel to the direction the PCL frame‐mediated tensile forces, with very few branching structures observed. Treatment of the 3D bioprinted constructs with traction inhibitors resulted in a significant reduction in length of vessel‐like networks. The 3D bioprinted constructs also had better lumen formation, increased collagen deposition, more elaborate actin networks, and well‐aligned matrix fibers due to the increased cell‐mediated traction forces present compared to the non‐anchored, floating control constructs. This study showed that cell traction forces from the actomyosin complex are critical for vascular network assembly in 3D bioprinted tissue. Strategies involving the use of cell‐mediated traction forces may be promising for the development of bioprinting approaches for fabrication of vascularized tissue constructs.

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Section: Discussionmentioning

confidence: 99%

ECM concentration and cell‐mediated traction forces play a role in vascular network assembly in 3D bioprinted tissue

Zhang

Varkey

Zhan

et al. 2020

Biotech & Bioengineering

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“…[ 15–24 ] For example, Davidson et al found that networks of contractile endothelial cells with different morphologies could be generated by varying the extent to which cells were able to physically reorganize surrounding ECM fibers. [ 25 ] Brownfield et al also found that mammary epithelial organoids reorganize and align collagen I fibers through cell contractility, and form multi‐cellular protrusions that follow preferentially along the axis of ECM alignment. [ 26 ] However, in neither example was the resulting cell network geometry spatially designed or predictable.…”

Section: Figurementioning

confidence: 99%

Guiding Cell Network Assembly using Shape‐Morphing Hydrogels

et al. 2020

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Forces and relative movement between cells and extracellular matrix (ECM) are crucial to the self‐organization of tissues during development. However, the spatial range over which these dynamics can be controlled in engineering approaches is limited, impeding progress toward the construction of large, structurally mature tissues. Herein, shape‐morphing materials called “kinomorphs” that rationally control the shape and size of multicellular networks are described. Kinomorphs are sheets of ECM that change their shape, size, and density depending on patterns of cell contractility within them. It is shown that these changes can manipulate structure‐forming behaviors of epithelial cells in many spatial locations at once. Kinomorphs are built using a new photolithographic technology to pattern single cells into ECM sheets that are >10× larger than previously described. These patterns are designed to partially mimic the branch geometry of the embryonic kidney epithelial network. Origami‐inspired simulations are then used to predict changes in kinomorph shapes. Last, kinomorph dynamics are shown to provide a centimeter‐scale program that sets specific spatial locations in which ≈50 µm‐diameter epithelial tubules form by cell coalescence and structural maturation. The kinomorphs may significantly advance organ‐scale tissue construction by extending the spatial range of cell self‐organization in emerging model systems such as organoids.

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“…At high pre-existing fibre densities (like in a conventional collagen I gel) cells stay unorganized. At lower densities of pre-formed fibres (but still the right stiffness of the gel), endothelial cells have recently been shown to align to these fibres (9). At a low cell density, we make a similar observation on collagen: cells align to preformed fibres.…”

Section: Discussionmentioning

confidence: 99%

“…This has, to date, largely been ascribed to shear stress exerted via blood flow (5). However, there are also numerous reports showing that endothelial cells respond to biophysical confinements (6), matrix stiffness (7, 8), and fibrous topography (9, 10). Furthermore, endothelial cells are able to deform collagen I gels (11) and thereby to communicate mechanically (12).…”

Section: Introductionmentioning

confidence: 99%

Cell based strain stiffening of a non-fibrous matrix as organizing principle for morphogenesis

Rüdiger

Kick

Goychuk

et al. 2019

Preprint

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Endothelial tube formation on a reconstituted extracellular matrix (Matrigel) is a wellestablished in vitro model for studying the processes of angiogenesis and vasculogenesis. However, to date, the organizing principles that underlie the morphogenesis of this network, and that shape the initial process of cell-cell finding remain elusive. Furthermore, it is unclear how in vitro results extrapolate to in vivo morphogenesis. Here, we identify a mechanism that allows cells to form networks by mechanically reorganizing and stiffening their extracellular matrix, independent of chemical guidance cues. Interestingly, we find that this cellular self-organization strongly depends on the connectivity and topology of the surrounding matrix, as well as on cell contractility and cell density. Cells rearrange the matrix, and form bridges of matrix material that are stiffer than their surroundings, thus creating a durotactic track for the initiation of cell-cell contacts. This contractility-based communication via strain stiffening and matrix rearrangement might be a general organizing principle during tissue development or regeneration.3 Significance StatementIn addition to chemotactic gradients, biomechanical cues are important for guiding biological pattern formation. Self-assembly of cells has often been ascribed to reorganization of collagen fibres in the extracellular matrix. However, the basement membrane surrounding vascular cells, is per se non-fibrous. Here, we find that this difference in matrix topology can crucially influence cell behaviour and pattern formation. In a homogeneously elastic environment like the basement membrane, endothelial cells rearrange extracellular matrix proteins by contractile force, forming stiff intercellular bridges as tracks for cell-cell contacts. Our findings shine some light why there is a lot of merit in having multiple approaches to matrix elasticity (like continuum theories or dilated network approaches). Our observations might help to understand why vascular nets look different in different tissues and after rearrangement of the extracellular matrix during disease.

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Cell force-mediated matrix reorganization underlies multicellular network assembly

Cited by 78 publications

References 59 publications

ECM concentration and cell‐mediated traction forces play a role in vascular network assembly in 3D bioprinted tissue

ECM concentration and cell‐mediated traction forces play a role in vascular network assembly in 3D bioprinted tissue

Guiding Cell Network Assembly using Shape‐Morphing Hydrogels

Cell based strain stiffening of a non-fibrous matrix as organizing principle for morphogenesis

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