Rap1 deficiency-provoked paracrine dysfunction impairs immunosuppressive potency of mesenchymal stem cells in allograft rejection of heart transplantation

Rap1 deficiency-provoked paracrine dysfunction impairs immunosuppressive potency of mesenchymal stem cells in allograft rejection of heart transplantation
Title:
Rap1 deficiency-provoked paracrine dysfunction impairs immunosuppressive potency of mesenchymal stem cells in allograft rejection of heart transplantation
Other Titles:
Cell Death & Disease
Keywords:
Publication Date:
07 March 2018
Citation:
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
Abstract:
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
License type:
http://creativecommons.org/licenses/by/4.0/
Funding Info:
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.).
Description:
ISSN:
2041-4889
Files uploaded:

File Size Format Action
174-s41419-018-0414-3.pdf 3.86 MB PDF Open