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Cell migration: implications for repair and regeneration in joint disease

Abstract

Connective tissues within the synovial joints are characterized by their dense extracellular matrix and sparse cellularity. With injury or disease, however, tissues commonly experience an influx of cells owing to proliferation and migration of endogenous mesenchymal cell populations, as well as invasion of the tissue by other cell types, including immune cells. Although this process is critical for successful wound healing, aberrant immune-mediated cell infiltration can lead to pathological inflammation of the joint. Importantly, cells of mesenchymal or haematopoietic origin use distinct modes of migration and thus might respond differently to similar biological cues and microenvironments. Furthermore, cell migration in the physiological microenvironment of musculoskeletal tissues differs considerably from migration in vitro. This Review addresses the complexities of cell migration in fibrous connective tissues from three separate but interdependent perspectives: physiology (including the cellular and extracellular factors affecting 3D cell migration), pathophysiology (cell migration in the context of synovial joint autoimmune disease and injury) and tissue engineering (cell migration in engineered biomaterials). Improved understanding of the fundamental mechanisms governing interstitial cell migration might lead to interventions that stop invasion processes that culminate in deleterious outcomes and/or that expedite migration to direct endogenous cell-mediated repair and regeneration of joint tissues.

Key points

  • Interstitial cell migration in the fibrous microenvironments of intra-articular tissues is regulated by biophysical and biochemical factors.

  • Immune cells are recruited to and retained within the synovium by inflammatory cytokines and chemokines in rheumatic disorders.

  • High matrix density and stiffness of adult dense connective tissues restrict the mobility of endogenous cells, impeding wound healing after injury.

  • Early cell migration into biomaterial scaffolds is a critical but challenging step towards engineering functional musculoskeletal tissues.

  • Targeted strategies that limit inflammatory cell invasion while promoting the migration of endogenous reparative cells might enhance joint tissue formation and regeneration.

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Fig. 1: Connective tissue type and migration capacity.
Fig. 2: Cell migration during joint development, disease and repair.
Fig. 3: Designing engineered scaffolds to promote cell migration and tissue repair.

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Acknowledgements

The work of F.Q., F.G. and R.L.M. is supported by the US National Institutes of Health (AR060719, AR056624, EB008722, AR50245, AR48852, AG46927, AG15768, AR48182, AR067467 and AR057235), the US Department of Veterans’ Affairs (I01 RX000174), the Arthritis Foundation, the Nancy Taylor Foundation for Chronic Diseases and the Collaborative Research Center of the AO Foundation in Davos.

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Nature Reviews Rheumatology thanks D. Grande and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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The authors contributed equally to all aspects of the article.

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Correspondence to Farshid Guilak or Robert L. Mauck.

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Glossary

Stress fibre

Contractile bundles in non-muscle cells composed of actin filaments and non-muscle myosin II; myosin motor activity results in contraction of the actomyosin bundles.

Micromechanics

The mechanical properties of a material assessed at a local level (that is, at the micrometre scale). This approach can identify heterogeneities in materials or tissues that are indicative of the constituent materials and their properties at that location.

Microstructure

The microscopic structure of a material or tissue.

Chemotaxis

Directional cell movement along a soluble biochemical gradient.

Haptotaxis

Directional cell movement along a substrate-bound insoluble gradient.

Collective migration

The process by which a group of cells move together while maintaining cell–cell contact.

Tensile modulus

Young’s modulus of a material evaluated in tension (that is, a measurement of tensile strength, which is the ability of a material to withstand being stretched).

Compressive modulus

Young’s modulus of a material evaluated in compression (that is, a measurement of compressive strength, which is the ability of a material to withstand being compressed).

Shear modulus

Young’s modulus of a material evaluated in shear (that is, a measurement of the shear strength, which is the ability of a material to withstand forces that can cause the internal structure of the material to slide against itself).

Young’s modulus

A mechanical property that defines the relationship between stress (force per unit area) and strain (proportional deformation) of a linearly elastic material during uniaxial deformation (also referred to as the elastic modulus; measured in MPa). Although commonly referred to as tissue stiffness or rigidity, these two terms are actually structural properties (that is, dependent on the size and shape of the tissue) and are not inherent material properties.

Contact guidance

The response of cells to topographic cues; the direction of cell alignment and migration is affected by geometrical patterns such as grooves or fibres.

Pannus

An abnormal layer of fibrovascular tissue, which can occur in rheumatoid arthritis.

Heterotopic ossification

The presence of bone in soft tissue where bone does not normally exist.

Scar tissue

Dense fibrous tissue that replaces original tissue during wound healing; the scar tissue is generally disordered and does not match the original tissue in terms of the biochemical content or mechanical properties.

Adhesion

Abnormal formation of scar tissue after injury that connects normally separated tissues and impedes joint motion.

Micromoulding

A technique for generating microstructures using moulds with micrometre-scale features.

Photolithography

A technique that uses light to transfer geometric patterns from a photomask (an opaque plate that enables light to shine through in a defined pattern) to a light-sensitive chemical on a substrate.

Electrospinning

A technique that produces nanofibres by charging and pulling a polymer solution through a spinneret under a high-voltage electrical field.

Rapid prototyping

A group of techniques for constructing a 3D product using computer-aided design (for example, 3D printing).

Anisotropic

Describes mechanical and physical properties that vary on the basis of the testing direction.

Porogens

Space-filling particles used to create porous materials, which are later removed to generate voids.

Bioinks

Extrudable polymer solutions used in 3D bioprinting that can contain cells and/or other biologics that can solidify after printing.

Stress relaxation

A time-dependent decrease in stress of a material in response to the same level of strain.

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Qu, F., Guilak, F. & Mauck, R.L. Cell migration: implications for repair and regeneration in joint disease. Nat Rev Rheumatol 15, 167–179 (2019). https://doi.org/10.1038/s41584-018-0151-0

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