Abstract
IntroductionOsteoarthritis (OA) is associated with chronic inflammation, and mesenchymal stromal cells (MSCs) have been shown to provide pain relief and reparative effects in clinical investigations. MSCs are often delivered with hyaluronic acid (HA), although the combined mechanism of action is not fully understood; we thus investigated the immunomodulatory effects of combining MSCs with different molecular weights (MW) of HA.MethodsHAs with MWs of 1.6 MDa (hHA), 150 kDa or 7.5 kDa, were added to MSCs alone or MSC-immune cell co-cultures. Gene expression analyses, flow cytometry and cytokine measurements were assessed to determine the effect of HAs on the MSC interactions with immune cells.ResultsMSCs in the presence of HAs, in both normal and lymphocyte-conditioned medium, showed negligible changes in gene expression. While addition of hHA resulted in increased proliferation of activated lymphocytes, both in the presence and absence of MSCs, the overall combined effect was a more regulated, homeostatic one; this was supported by higher ratios of secreted IL10/IFNγ and IL10/IL2, in lymphocyte cultures, than with lower MW HAs or no HA, both in the presence and absence of MSCs. In addition, examination of monocyte-derived macrophages showed an increased M2 macrophage frequency (CD14+CD163+CD206+) in the presence of hHA, both with and without MSCs.ConclusionshHA produces a less pro-inflammatory environment than lower MW HAs. Moreover, combining hHA with MSCs has an additive effect on the MSC-mediated immunomodulation, suggestive of a more potent combination treatment modality for OA.
Highlights
Osteoarthritis (OA) is associated with chronic inflammation, and mesenchymal stromal cells (MSCs) have been shown to provide pain relief and reparative effects in clinical investigations
While addition of hHA resulted in increased proliferation of activated lymphocytes, both in the presence and absence of MSCs, the overall combined effect was a more regulated, homeostatic one; this was supported by higher ratios of secreted IL10/interferon γ (IFNγ) and IL10/IL2, in lymphocyte cultures, than with lower molecular weights (MW) hyaluronic acid (HA) or no HA, both in the presence and absence of MSCs
OA has the highest prevalence among arthritis types, with about 12% of the senior US population suffering from symptomatic knee OA [4]
Summary
HAs with MWs of 1.6 MDa (hHA), 150 kDa or 7.5 kDa, were added to MSCs alone or MSCimmune cell co-cultures. Native HAs of 1.6 MDa (hHA), 150 kDa and 7.5 kDa HA, derived from Streptococcus Pyogenes, were obtained from Lifecore Biomedical (Chaska, MN). The University Health Network Research Ethics Board approved the acquisition of human tissues (bone marrow and blood, both acquired from consenting donors at Princess Margaret Hospital): approval #s 06-446-CE and 14-7483-AE, respectively. MSCs were acquired as previously described [38] from fresh bone marrow drawn from the iliac crest of consenting donor volunteers, and expanded (up to passage 4–6) using MSC growth medium: low glucose DMEM supplemented with 10% fetal bovine serum (FBS, screened for MSC growth). MSCs were cryopreserved and thawed at least 3 days before the start of an experiment
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