title: A Systematic Study of the Effect of Different Molecular Weights of Hyaluronic Acid on Mesenchymal Stromal Cell-Mediated Immunomodulation.
abstract: BACKGROUND
  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. 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.
  
  
  METHODS
  HAs 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.
  
  
  RESULTS
  MSCs 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.
  
  
  CONCLUSIONS
  hHA 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.
authors.affiliation: The Arthritis Program, Toronto Western Hospital, Toronto, ON, Canada.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Gómez-Aristizábal
authors.affiliation: Cell Therapy Program, Princess Margaret Cancer Centre, Toronto, ON, Canada.
authors.forename: Kyung-Phil
authors.initials: KP
authors.lastname: Kim
authors.affiliation: The Arthritis Program, Toronto Western Hospital, Toronto, ON, Canada.|Cell Therapy Program, Princess Margaret Cancer Centre, Toronto, ON, Canada.|Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sowmya
authors.initials: S
authors.lastname: Viswanathan
mesh_terms: D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D004353:Drug Evaluation, Preclinical; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry / Q000494:pharmacology*; D007155:Immunologic Factors / Q000737:chemistry / Q000494:pharmacology*; D056747:Immunomodulation; D008264:Macrophages / Q000502:physiology; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000502:physiology*; D008970:Molecular Weight; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000502:physiology
chemical_list: D007155:Immunologic Factors; D006820:Hyaluronic Acid
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