Macrophage depletion impairs neonatal tendon regeneration

Abstract

Tendons are dense connective tissues that transmit muscle forces to the skeleton. After adult injury, healing potential is generally poor and dominated by scar formation. Although the immune response is a key feature of healing, the specific immune cells and signals that drive tendon healing have not been fully defined. In particular, the immune regulators underlying tendon regeneration are almost completely undetermined due to a paucity of tendon regeneration models. Using a mouse model of neonatal tendon regeneration, we screened for immune-related markers and identified upregulation of several genes associated with inflammation, macrophage chemotaxis, and TGFβ signaling after injury. Depletion of macrophages using AP20187 treatment of MaFIA mice resulted in impaired functional healing, reduced cell proliferation, reduced ScxGFP+ neo-tendon formation, and altered tendon gene expression. Collectively, these results show that inflammation is a key component of neonatal tendon regeneration and demonstrate a requirement for macrophages in effective functional healing.

Oxo-M and 4-PPBP Delivery via Multi-Domain Peptide Hydrogel Toward Tendon Regeneration

“…Collective experimental evidences in several previous studies support the temporal roles of inflammatory of M1 macrophages and anti-inflammatory M2 macrophages in the early and late phases of tendon healing, respectively (35,(38)(39)(40). Excessive or prolonged M1 macrophages are closely involved with inflammation and scarring, whereas M2 macrophages play essential roles in matrix synthesis and remodeling (35,(38)(39)(40). Thus, prolonged activities of Oxo-M and 4-PPBP via controlled delivery with MDP may have promoted tendon healing by attenuating M1-mediated inflammation and M2-mediated anti-inflammatory cytokines and matrix remodeling.…”

“…Our in vitro data suggest that Oxo-M and 4-PPBP may interfere with M1 polarization while promoting M2 polarization. Collective experimental evidences in several previous studies support the temporal roles of inflammatory of M1 macrophages and anti-inflammatory M2 macrophages in the early and late phases of tendon healing, respectively (35,(38)(39)(40). Excessive or prolonged M1 macrophages are closely involved with inflammation and scarring, whereas M2 macrophages play essential roles in matrix synthesis and remodeling (35,(38)(39)(40).…”

CCR2 identifies tendon resident macrophage and T cell populations while CCR2 deficiency impedes late tendon healing

“…Macrophage depletion in adult tendon promoted cell proliferation and ECM accumulation but lead to inferior tensile strength(14). Consistent with this, macrophage depletion in neonatal Achilles tendons resulted in impaired functional healing, however cell proliferation was reduced (9). In addition, extracellular vesicles derived from human mesenchymal stem cells (MSCs) primed macrophages towards an M2 anti-inflammatory phenotype that improved Achilles tendon biomechanics following injury (15).…”

“…While tissue resident macrophages are thought to be a relatively small population of the tendon cell environment during homeostasis (8), there is a robust increase in extrinsic macrophage infiltration to the tendon after acute injury, which is critical for initiation of the inflammatory phase of healing (1,4,5,9). Macrophages are a dynamic cell population that interact with tissue resident cell populations, extrinsic immune cells, and extracellular proteins (6,7,10).…”

Reprogramming adult tendon healing using regenerative neonatal regulatory T cells

“…neonatal heart, neonatal tendon, adult muscle, adult bone) and regenerative organisms (e.g. salamander, zebrafish), depletion of macrophages results in failed regeneration [12][13][14][15][16] ; however macrophages are also indispensable for scar-mediated healing 17,18 . In adult tissues, macrophage polarization toward a Ly-6C lo anti-inflammatory profile appears to promote tissue healing 12,19,20 ; however how this polarization is controlled has not been fully defined.…”