The effects of hyaluronan on the adipose-derived stem cell secretome for the treatment of osteoarthritis

Osteoarthritis (OA) can be a debilitating degenerative disease and is the most common form of arthritic disease. There is a general consensus that current non-surgical therapies are insufficient for younger OA sufferers who are not candidates for knee arthroplasties. Adipose-derived mesenchymal stem cell (MSCs) therapy for the treatment of OA can slow disease progression and lead to neocartilage formation. Using Hyaluronan (HA) for delivery of MSC therapy in OA is widespread with no consideration of altered MSC function. The mechanism of action of MSCs is secretion driven. Therefore we sought to elucidate the effects of different concentrations of hyaluronan on MSC growth kinetics and evaluate the effect on the MSC secretome. Using a range of clinically relevant preparations, a titration of hyaluronan concentrations, we assessed MSC adherence and proliferation on both culture plastic surfaces and a novel cartilage-adhesion assay. We employed an adherence time-course and dispersion imaging techniques to assess MSC binding to cartilage. Our data showed HA had profound dose-dependent effects on early growth kinetics and the secretome of MSCs at concentrations up to the hyaluronan entanglement point at 1 mg/mL. At higher concentrations viscosity effects outweighed any benefit of additional HA. The novel cartilage-adhesion assay revealed for the first time that HA-primed MSCs can increase cell attachment to cartilage and that the presence of HA did not. In conclusion, the investigation showed HA can have profound dose-dependent effects on MSCs. Although early data cytokine data suggested HA would negatively impact MSC mode of action, functional assessments of human osteoarthritic cartilage and synovium demonstrated HA culture modulated negative effects produce by the MSC secretome. Thus we have shown through exploration of the MSC secretome that MSCs cultured in HA would have a synergistic effect in MSC therapy for the treatment of knee OA.