Harnessing the secreted extracellular matrix to engineer tissues

Blache, Ulrich; Stevens, Molly M.; Gentleman, Eileen

doi:10.1038/s41551-019-0500-6

Cited by 76 publications

(63 citation statements)

References 66 publications

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“…[ 6 ] These recent findings clearly suggest that a better understanding of cell‐derived ECM within synthetic hydrogels is required, which might then also provide an opportunity to harness secreted ECM for the engineering of tissues. [ 7 ]…”

Section: Introductionmentioning

confidence: 99%

Extracellular Matrix Production by Mesenchymal Stromal Cells in Hydrogels Facilitates Cell Spreading and Is Inhibited by FGF‐2

Horton

Vallmajó-Martín

Martín

et al. 2020

Adv Healthcare Materials

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In native tissues, the interaction between cells and the surrounding extracellular matrix (ECM) is reciprocal, as cells not only receive signals from the ECM but also actively remodel it through secretion of cell‐derived ECM. However, very little is known about the reciprocal interaction between cells and their secreted ECM within synthetic biomaterials that mimic the ECM for use in engineering of tissues for regenerative medicine or as tissue models. Here, poly(ethylene glycol) (PEG) hydrogels with fully defined biomaterial properties are used to investigate the emerging role of cell‐derived ECM on culture outcomes. It is shown that human mesenchymal stromal cells (MSCs) secrete ECM proteins into the pericellular space early after encapsulation and that, even in the absence of material‐presented cell adhesion motifs, cell‐derived fibronectin enables cell spreading. Then, it is investigated how different culture conditions influence MSC ECM expression in hydrogels. Most strikingly, it is found by RNA sequencing that the fibroblast growth factor 2 (FGF‐2) changes ECM gene expression and, in particular, decreases the expression of structural ECM components including fibrillar collagens. In summary, this work shows that cell‐derived ECM is a guiding cue in 3D hydrogels and that FGF‐2 is a potentially important ECM regulator within bioengineered cell and tissue systems.

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Section: Introductionmentioning

confidence: 99%

Extracellular Matrix Production by Mesenchymal Stromal Cells in Hydrogels Facilitates Cell Spreading and Is Inhibited by FGF‐2

Horton

Vallmajó-Martín

Martín

et al. 2020

Adv Healthcare Materials

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“…Beyond the provisional synthetic matrix of hydrogels, ECM secreted by cells, such as collagen type-I, is a tunable factor within engineered hydrogels and can influence hydrogel success [61][62][63] . In this work, we observed collagen type-I in the pericellular matrix of hMSCs in 3D culture with or without mfCMPs yet with significantly increased cell elongation in the presence of assembled mfCMPs, representing a cellular response to mfCMPs that may be a function of both ECM composition and structure.…”

Section: Discussionmentioning

confidence: 99%

Success Criteria for Preclinical Testing of Cell-Instructive Hydrogels for Tendon Regeneration

Locke

Ford

Silbernagel

et al. 2020

Preprint

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Tendon injuries are difficult to heal in part because intrinsic tendon healing, which is dominated by scar tissue formation, does not effectively regenerate the native structure and function of healthy tendon. Further, many current treatment strategies also fall short of producing regenerated tendon with the native properties of healthy tendon. There is increasing interest in the use of cell-instructive strategies to limit the intrinsic fibrotic response following injury and improve the regenerative capacity of tendon in vivo. We have established multi-functional, cell-instructive hydrogels for treating injured tendon that afford tunable control over the biomechanical, biochemical, and structural properties of the cell microenvironments. Specifically, we incorporated integrin-binding domains (RGDS) and assembled multi-functional collagen mimetic peptides (mfCMPs) that enable cell adhesion and elongation of stem cells within synthetic hydrogels of designed biomechanical properties and evaluated these materials using targeted success criteria developed for testing in mechanically-demanding environments like tendon healing. The in vitro and in situ success criteria were determined based on systematic reviews of the most commonly reported outcome measures of hydrogels for tendon repair and established standards for testing of biomaterials. We then showed, using validation experiments, that multi-functional and synthetic hydrogels meet these criteria. Specifically, these hydrogels have mechanical properties comparable to developing tendon; are non-cytotoxic both in 2D bolus exposure (hydrogel components) and 3D encapsulation (full hydrogel); are formed, retained, and visualized within tendon defects over time (two-weeks); and provide mechanical support to tendon defects at the time of injection and in situ formation. Ultimately, the in vitro and in situ success criteria evaluated in this study were designed for preclinical research to rigorously test the potential to achieve successful tendon repair prior to in vivo testing and indicate the promise of multi-functional and synthetic hydrogels for continued translation.

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“…This work and other studies highlight the importance of elucidating these complex mechanistic details, ultimately, with the objective of designing "smart" hydrogel platforms able to dictate cell-based matrix remodeling and protein secretion. [265] In this Progress Report, we have defined intrinsic triggers as events that initiate gelation by directly altering the base material or the reaction kinetics. Intrinsic triggers include alterations in temperature or solution pH, and the input of light or enzymes.…”

Section: (16 Of 22)mentioning

confidence: 99%

Tailoring Gelation Mechanisms for Advanced Hydrogel Applications

Nele

Wojciechowski

Armstrong

et al. 2020

Adv Funct Materials

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191

100

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Hydrogels are one of the most commonly explored classes of biomaterials. Their chemical and structural versatility has enabled their use across a wide range of applications, including tissue engineering, drug delivery, and cell culture. Hydrogels form upon a sol-gel transition, which can be elicited by different triggers designed to enable precise control over hydrogelation kinetics and hydrogel structure. The chosen hydrogelation trigger and chemistry can have a profound effect on the success of the targeted application. In this Progress Report, a critical overview of recent advances in hydrogel design is presented, with a focus on the available strategies used to trigger the formation of hydrogel networks (e.g., temperature, light, ultrasound). These triggers are presented within a new classification system, and their suitability for six key hydrogel-based applications is assessed. This Progress Report is intended to guide trigger selection for new hydrogel applications and inspire the rational design of new hydrogelation trigger mechanisms.

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Harnessing the secreted extracellular matrix to engineer tissues

Cited by 76 publications

References 66 publications

Extracellular Matrix Production by Mesenchymal Stromal Cells in Hydrogels Facilitates Cell Spreading and Is Inhibited by FGF‐2

Extracellular Matrix Production by Mesenchymal Stromal Cells in Hydrogels Facilitates Cell Spreading and Is Inhibited by FGF‐2

Success Criteria for Preclinical Testing of Cell-Instructive Hydrogels for Tendon Regeneration

Tailoring Gelation Mechanisms for Advanced Hydrogel Applications

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