Immunomodulation in mesenchymal stem cell therapy for osteoarthritis: mechanistic insights on the role of cell death and engraftment
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2018-11-02Author
Mancuso, Patrizio
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Abstract
Osteoarthritis (OA) is a degenerative pathology of the articular cartilage causing chronic
pain and disability in millions of individuals. In OA synovia, resident macrophages and
infiltrated lymphocytes contribute to the disease progression by releasing catabolic
mediators that interfere with the reparative process. Mesenchymal stem cells (MSCs)
possess the capacity to release immune-modulating cytokines when licensed by proinflammatory
stimuli. They were also proven to promote regeneration in pre-clinical
models of OA and to improve disease scores in small-scale clinical trials.
To assess whether MSCs act by alleviating synovitis, a novel approach was optimised to
retrieve GFP+ cells after intra-articular (IA) injection into a murine model of collagenaseinduced
OA (CIOA). MSCs were separated from knee digests by FACS-coupled cell
sorting and expanded in culture for further characterisation. Retrieval and processing did
not affect their proliferation rates or clonogenicity but slightly altered their differentiative
potential.
CIOA-retrieved MSCs had no effect on syngeneic T cells in co-culture experiments.
However, their conditioned medium (CM) caused polarisation of in vitro activated
macrophages towards an M2 immunomodulatory phenotype, with lower expression of
MHC-II and CD86 and increased secretion of IL-10. The immunomodulatory effect of
CIOA-challenged MSCs was significant, compared to both naïve MSCs and MSCs injected
in sham-treated animals.
As only 1.627% of the implanted MSCs was successfully retrieved, it was postulated that
MSCs act via a hit-and-run mechanism, with release of cytokines following rapid
apoptosis. In vitro-induced apoptosis promoted a similar trophic-mediated M2 switch,
resulting in significantly higher IL-10 secretion from macrophages. However, apoptotic
MSCs also prevented proliferation and activation of co-cultured lymphocytes.
The presented data demonstrates that, following IA administration, a large proportion of
MSCs undergoes apoptosis and exert non-specific immunomodulatory effects. A smaller
percentage acquire a licensed phenotype which aids in the resolution of synovitis through
a paracrine mechanism indirectly mediated by reprogrammed macrophages.