Ding, Y., Liang, X., Zhang, Y. et al. Rap1 deficiency-provoked paracrine dysfunction impairs immunosuppressive potency of mesenchymal stem cells in allograft rejection of heart transplantation. Cell Death Dis 9, 386 (2018). https://doi.org/10.1038/s41419-018-0414-3
Immunomodulatory activity of mesenchymal stem cells (MSCs) is largely mediated by paracrine factors. Our previous studies showed that activation of nuclear factor-kappa B (NF-κB) regulates cytokine/growth factor secretion by MSCs. This study aimed to elucidate the role of Rap1 (repressor/activator protein), a novel modulator involved in the NF-κB pathway, in regulating the immunomodulatory potency of MSCs in acute allograft rejection of heart transplantation. The immunosuppressive potency of wild-type MSCs (WT-MSCs) or Rap1-deficient MSCs (Rap1−/−-MSCs) was examined in mice with acute allograft rejection following heart transplantation. With a combination of immunosuppressant rapamycin at a dose of 1 mg/kg/d, WT-MSCs notably prolonged the survival of the transplanted heart compared with Rap1−/−-MSCs. Rap1−/−-MSCs displayed a marked insensitivity to inhibit the mixed lymphocyte reaction (MLR) due to impaired cytokine production and a significantly reduced activity of NF-κB signaling in vitro. Finally, transplantation of encapsulated WT-MSCs greatly prolonged the survival of the heart allograft compared with encapsulated Rap1−/−-MSCs. Our results indicate that Rap1 is essential to maintain the immunomodulatory function of MSCs. Deletion of Rap1 results in impaired immunomodulatory function of MSCs
This study was partly supported by grants from the National Natural Science Foundation of China (31270967 and 31571407 to Q.L.; 81500207 to X.L.); Hong Kong RGC/GRF (HKU 17120517; HKU17113816 to Q.L.); The key grant from the Science and Technology Foundation of Guangdong Province of China (2015B020225001); Small project funding from The University of Hong Kong (201409176221 to Y.Z.); and Program for Young Excellent Talents in Tongji University (2015KJ073 to X.L.).