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A growth factor-induced, spatially organizing cytoskeletal module enables rapid and persistent fibroblast migration.

ABSTRACT: Directional migration requires robust front/back polarity. We find that fibroblasts treated with platelet-derived growth factor (PDGF) and prepolarized by plating on a fibronectin line substrate exhibit persistent migration for hours. This does not occur in the absence of PDGF or on uniformly coated fibronectin substrates. Persistent migration arises from establishment of two functional modules at cell front and back. At the front, formation of a zone containing podosome-like structures (PLS) dynamically correlates with low RhoA and myosin activity and absence of a contractile lamella. At the back, myosin contractility specifically controls tail retraction with minimal crosstalk to the front module. The PLS zone is maintained in a dynamic steady state that preserves size and position relative to the cell front, allowing for long-term coordination of front and back modules. We propose that front/back uncoupling achieved by the PLS zone is crucial for persistent migration in the absence of directional cues.

SUBMITTER: Martin K

PROVIDER: S-EPMC4385272 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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A growth factor-induced, spatially organizing cytoskeletal module enables rapid and persistent fibroblast migration.

Martin Katrin K Vilela Marco M Jeon Noo Li NL Danuser Gaudenz G Pertz Olivier O

Developmental cell 20140901 6

Directional migration requires robust front/back polarity. We find that fibroblasts treated with platelet-derived growth factor (PDGF) and prepolarized by plating on a fibronectin line substrate exhibit persistent migration for hours. This does not occur in the absence of PDGF or on uniformly coated fibronectin substrates. Persistent migration arises from establishment of two functional modules at cell front and back. At the front, formation of a zone containing podosome-like structures (PLS) dy ...[more]

PMID: 25268172

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Project description:Hydrogels are commonly used in regenerative medicine for the delivery of growth factors (GFs). The spatial and temporal presentations of GFs are critical for directing regenerative processes, yet conventional hydrogels do not enable such control. We have developed a composite hydrogel, termed an acoustically-responsive scaffold (ARS), where release of a GF is non-invasively and spatiotemporally-controlled using focused ultrasound. The ARS consists of a fibrin matrix doped with a GF-loaded, phase-shift emulsion. The GF is released when the ARS is exposed to suprathreshold ultrasound via a mechanism termed acoustic droplet vaporization. In this study, we investigate how different spatial patterns of suprathreshold ultrasound can impact the biological response upon in vivo implantation of an ARS containing basic fibroblast growth factor (bFGF). ARSs were fabricated with either perfluorohexane (bFGF-C6-ARS) or perflurooctane (bFGF-C8-ARS) within the phase-shift emulsion. Ultrasound generated stable bubbles in bFGF-C6-ARS, which inhibited matrix compaction, whereas transiently stable bubbles were generated in bFGF-C8-ARS, which decreased in height by 44% within one day of implantation. The rate of bFGF release and distance of host cell migration were up to 6.8-fold and 8.1-fold greater, respectively, in bFGF-C8-ARS versus bFGF-C6-ARS. Ultrasound increased the formation of macropores within the fibrin matrix of bFGF-C8-ARS by 2.7-fold. These results demonstrate that spatially patterning suprathreshold ultrasound within bFGF-C8-ARS can be used to elicit a spatially-directed response from the host. Overall, these findings can be used in developing strategies to spatially pattern regenerative processes. STATEMENT OF SIGNIFICANCE: Hydrogels are commonly used in regenerative medicine for the delivery of growth factors (GFs). The spatial and temporal presentations of GFs are critical for directing regenerative processes, yet conventional hydrogels do not enable such control. We have developed a composite hydrogel, termed an acoustically-responsive scaffold (ARS), where GF release is non-invasively and spatiotemporally-controlled using focused ultrasound. The ARS consists of a fibrin matrix doped with a phase-shift emulsion loaded with GF, which is released when the ARS is exposed to ultrasound. In this in vivo study, we demonstrate that spatially patterning ultrasound within an ARS containing basic fibroblast growth factor (bFGF) can elicit a spatially-directed response from the host. Overall, these findings can be used in developing strategies to spatially pattern regenerative processes.

Project description:Vascularization is a critical step following implantation of an engineered tissue construct in order to maintain its viability. The ability to spatially pattern or direct vascularization could be therapeutically beneficial for anastomosis and vessel in-growth. However, acellular and cell-based strategies to stimulate vascularization typically do not afford this control. We have developed an ultrasound-based method of spatially- controlling regenerative processes using acellular, composite hydrogels termed acoustically-responsive scaffolds (ARSs). An ARS consists of a fibrin matrix doped with a phase-shift double emulsion (PSDE). A therapeutic payload, which is initially contained within the PSDE, is released by an ultrasound-mediated process called acoustic droplet vaporization (ADV). During ADV, the perfluorocarbon (PFC) phase within the PSDE is vaporized into a gas bubble. In this study, we generated ex situ four different spatial patterns of ADV within ARSs containing basic fibroblast growth factor (bFGF), which were subcutaneously implanted in mice. The PFC species within the PSDE significantly affected the morphology of the ARS, based on the stability of the gas bubble generated by ADV, which impacted host cell migration. Irrespective of PFC, significantly greater cell proliferation (i.e., up to 2.9-fold) and angiogenesis (i.e., up to 3.7-fold) were observed adjacent to +ADV regions of the ARSs compared to -ADV regions. The morphology of the PSDE, macrophage infiltration, and perfusion in the implant region were also quantified. These results demonstrate that spatially-defined patterns of ADV within an ARS can elicit spatially-defined patterns of angiogenesis. Overall, these finding can be applied to improve strategies for spatially-controlling vascularization. STATEMENT OF SIGNIFICANCE: Vascularization is a critical step following implantation of an engineered tissue. The ability to spatially pattern or direct vascularization could be therapeutically beneficial for inosculation and vessel in-growth. However, acellular and cell-based strategies to stimulate vascularization typically do not afford this control. We have developed an ultrasound-based method of spatially-controlling angiogenesis using acellular, composite hydrogels termed acoustically-responsive scaffolds (ARSs). An ARS consists of a fibrin matrix doped with a phase-shift double emulsion (PSDE). An ultrasound-mediated process called acoustic droplet vaporization (ADV) was used to release basic fibroblast growth factor (bFGF), which was initially contained within the PSDE. We demonstrate that spatially-defined patterns of ADV within an ARS can elicit spatially-defined patterns of angiogenesis in vivo. Overall, these finding can improve strategies for spatially-controlling vascularization.

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A growth factor-induced, spatially organizing cytoskeletal module enables rapid and persistent fibroblast migration.

Publications

A growth factor-induced, spatially organizing cytoskeletal module enables rapid and persistent fibroblast migration.

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