Preconditioned or IL4-Secreting Mesenchymal Stem Cells Enhanced Osteogenesis at Different Stages. Tissue engineering. Part A Lin, T., Kohno, Y., Huang, J., Romero-Lopez, M., Maruyama, M., Ueno, M., Pajarinen, J., Nathan, K., Yao, Z., Yang, F., Wu, J., Goodman, S. B. 2019


Chronic inflammation-associated bone diseases involve continuous destruction and impaired regeneration of bone. Mesenchymal stem cell (MSC)-based therapy has great potential to modulate inflammatory responses and enhance tissue regeneration. We previously showed that lipopolysaccharide [LPS] plus TNF? preconditioned MSCs or genetically modified inflammation-sensing (driven by NF?B activation) IL4-secreting MSCs enhanced immunomodulation of macrophages to the more desired tissue repaired M2 type. In the current study, the paracrine regulation of therapeutic MSCs on the pro-inflammatory response and osteogenesis of macrophage-MSC co-cultures (representing endogenous cells) was examined using an in vitro transwell system. In the co-cultures, IL4-secreting MSCs decreased TNF? and iNOS expression, and increased Arginase 1 and CD206 expression in the presence of LPS-contaminated polyethylene particles. The preconditioned MSCs decreased TNF? and CD206 expression in the bottom MSC-macrophage co-cultures in the presence of contaminated particles. In osteogenesis assays, IL4-secreting MSCs decreased ALP expression, but increased alizarin red staining in the presence of contaminated particles. The preconditioned MSCs increased ALP and osteocalcin expression, and had no significant effect on alizarin red staining. These results suggest that potential treatments using preconditioned MSCs at an earlier stage, or IL4-secreting MSCs at a later stage could enhance bone regeneration in inflammatory conditions including periprosthetic osteolysis.

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