The aryl hydrocarbon receptor controls mesenchymal stromal cell-mediated immunomodulation via ubiquitination of eukaryotic elongation factor-2 kinase.

Mesenchymal stem cells (MSCs) have great therapeutic advantages due to their immunosuppressive properties. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor whose signaling plays an important role in the immune system. AHR may be involved in the regulation of MSC-associated immunomodulatory functions. However, the mechanisms by which AHR controls the immunosuppressive functions of MSCs are not well understood. Here, we report that Ahr-deficient MSCs show decreased therapeutic efficacy against graft-versus-host disease (GVHD) compared to wild-type (WT)-MSCs. This was probably due to decreased iNOS protein expression, which is a key regulatory enzyme in MSC immunomodulation. The expression of eukaryotic elongation factor 2 kinase (eEF2K), which inhibits the elongation stage of protein synthesis, is significantly increased in the Ahr-deficient MSCs. Inhibition of eEF2K restored iNOS protein expression. AHR is known to act as an E3 ligase together with CUL4B. We observed constitutive binding of AHR to eEF2K. Consequently, ubiquitination and degradation of eEF2K were inhibited in Ahr-deficient MSCs and by the AHR antagonist CH223191 in WT-MSCs. In summary, AHR regulates the immunomodulatory functions of MSCs through ubiquitination of eEF2K, thereby controlling iNOS protein synthesis and its product, nitric oxide levels.

Structural Femoral Shaft Allografts for Anterior Spinal Column Reconstruction in Osteoporotic Spines.

This study was to investigate the clinical and radiographical outcomes of anterior spinal column reconstruction using structural femoral shaft allografts in osteoporotic patients. Retrospective analyses of medical records, radiographic parameters, and postoperative complications were performed in twenty-one patients who underwent anterior spinal column reconstruction surgery for osteoporotic vertebral collapse or nonunion. Surgical invasiveness, clinical outcomes, postoperative complications, and radiographic outcomes were evaluated. Ambulatory status and back pain significantly improved. The Cobb's angle of segmental kyphosis significantly improved immediately after surgery with slight progression at the final follow-up. There were two cases of failed reconstruction with marked progression of kyphosis; both were related to loosening of screws rather than subsidence of the graft. Anterior spinal column reconstruction using femoral shaft allografts improved kyphosis and resulted in minimal subsidence and therefore is recommended as an effective treatment option for dealing with osteoporotic vertebral collapse and kyphotic deformity.