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.

Fig. 1 |. Connective tissue type and migration capacity.

Fibrous tissues can be grouped into three major categories: loose connective tissue, dense irregular connective tissue and dense regular connective tissue. Steric barriers to migration increase with matrix density and organization, such that mesenchymal cell mobility becomes severely restricted in dense regular connective tissues. ECM, extracellular matrix.

Fig. 2 |. Cell migration during joint development, disease and repair.

Cell migration is important during development, repair in response to injury and disease of various tissues in the knee joint. Meniscus progenitor cells migrate through loose mesenchyme along chemotactic gradients during tissue morphogenesis. After a meniscal tear, mature meniscal cells migrate through dense, aligned collagen fibres to initiate repair at the wound site. In rheumatoid arthritis (RA), immune cells enter via the blood vessels and cross the endothelium to invade the synovium in response to inflammatory cytokines. Migrating cells secrete matrix-degrading enzymes to facilitate passage, but uncontrolled enzyme production in RA might damage intra-articular tissues. ECM, extracellular matrix.

Fig. 3 |. Designing engineered scaffolds to promote cell migration and tissue repair.

a | Engineered replacements for intra-articular tissues require cells and scaffolds to withstand compressive and/or or tensile forces during joint loading. As such, crosslinked hydrogels (which resist compression) and aligned fibres (which resist tension) are often used for tissue engineering of cartilage and dense regular connective tissues such as meniscus and ligament, respectively. b | For all scaffolds, successful formation of functional tissues is achieved in part by considering the design of the biomaterial (such as the biochemical and biophysical aspects) to control cell behaviours such as adhesion, migration and differentiation. Furthermore, localized delivery of anti-inflammatory molecules might reduce the foreign body response and promote matrix synthesis by cells within the scaffold. To fine-tune the cellular response, biomaterials can be further modified to enable in situ cell reprogramming and/or cell-mediated scaffold remodelling (cell-responsive scaffolds).