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Enhancing Schwann cell migration using concentration gradients of laminin-derived peptides.

ABSTRACT: Neuroregeneration following peripheral nerve injury is largely mediated by Schwann cells (SC), the principal glial cell that supports neurons in the peripheral nervous system. Axonal regeneration in vivo is limited by the extent of SC migration into the gap between the proximal and distal nerve, however, little is known regarding the principal driving forces for SC migration. Engineered microenvironments, such as molecular and protein gradients, play a role in the migration of many cell types, including cancer cells and fibroblasts. However, haptotactic strategies have not been applied widely to SC. Herein, a series of tethered laminin-derived peptides were analyzed for their influence on SC adhesion, proliferation, and alignment. Concentration gradient substrates were fabricated using a controlled vapor deposition method, followed by covalent peptide attachment via a thiol-ene reaction, and characterized by X-ray photoelectron spectroscopy (XPS) and MALDI-MS imaging. While tethered RGD peptides supported SC adhesion and proliferation, concentration gradients of RGD had little influence on biased SC directional migration. In contrast, YIGSR promoted less SC attachment than RGD, yet YIGSR peptide gradients directed migration with a strong bias to the concentration profile. With YIGSR peptide, overall speed increased with the steepness of the peptide concentration profile. YIGSR gradients had no haptotactic effect on rat dermal fibroblast migration, in contrast to fibroblast migration on RGD gradients. The response of SC to these tethered peptide gradients will guide the development of translationally relevant constructs designed to facilitate endogenous SC infiltration into defects for nerve regeneration.

SUBMITTER: Motta CMM

PROVIDER: S-EPMC6868524 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Enhancing Schwann cell migration using concentration gradients of laminin-derived peptides.

Motta Cecilia M M CMM Endres Kevin J KJ Wesdemiotis Chrys C Willits Rebecca K RK Becker Matthew L ML

Biomaterials 20190704

Neuroregeneration following peripheral nerve injury is largely mediated by Schwann cells (SC), the principal glial cell that supports neurons in the peripheral nervous system. Axonal regeneration in vivo is limited by the extent of SC migration into the gap between the proximal and distal nerve, however, little is known regarding the principal driving forces for SC migration. Engineered microenvironments, such as molecular and protein gradients, play a role in the migration of many cell types, i ...[more]

PMID: 31302351

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Project description:BackgroundSuccessful nerve regeneration depends upon directed migration of morphologically specialized repair state Schwann cells across a nerve defect. Although several groups have studied directed migration of Schwann cells in response to chemical or topographic cues, the current understanding of how the mechanical environment influences migration remains largely understudied and incomplete. Therefore, the focus of this study was to evaluate Schwann cell migration and morphodynamics in the presence of stiffness gradients, which revealed that Schwann cells can follow extracellular gradients of increasing stiffness, in a form of directed migration termed durotaxis.MethodsPolyacrylamide substrates were fabricated to mimic the range of stiffness found in peripheral nerve tissue. We assessed Schwann cell response to substrates that were either mechanically uniform or embedded with a shallow or steep stiffness gradient, respectively corresponding to the mechanical niche present during either the fluid phase or subsequent matrix phase of the peripheral nerve regeneration process. We examined cell migration (velocity and directionality) and morphology (elongation, spread area, nuclear aspect ratio, and cell process dynamics). We also characterized the surface morphology of Schwann cells by scanning electron microscopy.ResultsOn laminin-coated polyacrylamide substrates embedded with either a shallow (?0.04 kPa/mm) or steep (?0.95 kPa/mm) stiffness gradient, Schwann cells displayed durotaxis, increasing both their speed and directionality along the gradient materials, fabricated with elastic moduli in the range found in peripheral nerve tissue. Uniquely and unlike cell behavior reported in other cell types, the durotactic response of Schwann cells was not dependent upon the slope of the gradient. When we examined whether durotaxis behavior was accompanied by a pro-regenerative Schwann cell phenotype, we observed altered cell morphology, including increases in spread area and the number, elongation, and branching of the cellular processes, on the steep but not the shallow gradient materials. This phenotype emerged within hours of the cells adhering to the materials and was sustained throughout the 24 hour duration of the experiment. Control experiments also showed that unlike most adherent cells, Schwann cells did not alter their morphology in response to uniform substrates of different stiffnesses.ConclusionThis study is notable in its report of durotaxis of cells in response to a stiffness gradient slope, which is greater than an order of magnitude less than reported elsewhere in the literature, suggesting Schwann cells are highly sensitive detectors of mechanical heterogeneity. Altogether, this work identifies durotaxis as a new migratory modality in Schwann cells, and further shows that the presence of a steep stiffness gradient can support a pro-regenerative cell morphology.

Dataset Information

Enhancing Schwann cell migration using concentration gradients of laminin-derived peptides.

Publications

Enhancing Schwann cell migration using concentration gradients of laminin-derived peptides.

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