Improved Osteogenesis by HVEM-Expressing Allogenic Bone Marrow-Derived Mesenchymal Stem Cells in an Immune Activation Condition and Mouse Femoral Defect Model.

Use of allogeneic mesenchymal stem cells (allo-MSCs) in bone tissue engineering strategies can overcome the limitations associated with autologous MSCs, but unfortunately, the immunogenicity of allo-MSCs leads to a high rate of rejection, unless immunosuppressive agents are used. B and T lymphocyte attenuator (BTLA) is a newly discovered immunoglobulin superfamily inhibitory receptor, and Herpesvirus-entry mediator (HVEM), a member of the tumor necrosis factor receptor family, is the only ligand of BTLA. Both BTLA and HVEM are widely expressed in B and T lymphocytes and other immune cells and play significant roles in the negative regulation of an immunoreaction. Therefore, we hypothesized that MSCs could be modified to maintain their bone differentiation ability through negative regulation of the immune response, and to test this hypothesis, we generated HVEM-expressing MSCs and tested their potential for osteogenic differentiation and bone repair in a simulated immune activation condition in vitro and in a mice femoral defect model. We found that osteogenic differentiation of allo-MSCs was decreased significantly in the activated immune microenvironment and that HVEM expression by allo-MSCs inhibited the immune response, resulting in improved osteogenic differentiation in vitro and new bone formation by allo-MSCs in a mouse femoral defect model. Our results also preliminarily suggested that the mechanism by which HVEM-expressing allo-MSCs overcome inflammation and enhance osteogenesis may be related to inhibition of interleukin-17. Overall, the data obtained in the present study provide support for the further development of HVEM-modified allo-MSCs as potentially ideal seed cells for bone tissue engineering applications.