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Abstract
Mesenchymal stem cell (MSC) exosome was previously shown to be effective in repairing
critical size osteochondral defects in an immunocompetent rat model. Here we investigate
the cellular processes modulated by MSC exosomes and the mechanism of action underlying
the exosome-mediated responses in cartilage repair. We observed that exosome-mediated
repair of osteochondral defects was characterised by increased cellular proliferation
and infiltration, enhanced matrix synthesis and a regenerative immune phenotype. Using
chondrocyte cultures, we could attribute the rapid cellular proliferation and infiltration
during exosome-mediated cartilage repair to exosomal CD73-mediated adenosine activation
of AKT and ERK signalling. Inhibitors of AKT or ERK phosphorylation suppressed exosome-mediated
increase in cell proliferation and migration but not matrix synthesis. The role of
exosomal CD73 was confirmed by the attenuation of AKT and ERK signalling by AMPCP,
a CD73 inhibitor and theophylline, an adenosine receptor antagonist. Exosome-treated
defects also displayed a regenerative immune phenotype characterised by a higher infiltration
of CD163+ regenerative M2 macrophages over CD86+ M1 macrophages, with a concomitant
reduction in pro-inflammatory synovial cytokines IL-1β and TNF-α. Together, these
observations demonstrated that the efficient osteochondral regeneration by MSC exosomes
was effected through a coordinated mobilisation of multiple cell types and activation
of several cellular processes.