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Cell Death Dis. 2018 Mar 7;9(3):386. doi: 10.1038/s41419-018-0414-3.

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

Ding Y1,2,3, Liang X2,4,5, Zhang Y2,6, Yi L7, Shum HC8, Chen Q8, Chan BP8, Fan H9, Liu Z4,9, Tergaonkar V10, Qi Z11, Tse HF12, Lian Q13,14,15.

Author information

1
Department of Organ Transplantation, Changzheng Hospital, Second Military Medical University, Shanghai, China.
2
Department of Medicine, The University of Hong Kong, Hong Kong SAR, China.
3
Organ Transplantation Institute of Xiamen University, Xiamen, Fujian Province, China.
4
Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
5
Clinical Translational Medical Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
6
Department of Emergency, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
7
Peking University Shenzhen Hospital, Shenzhen, China.
8
Department of Mechanical Engineering, The University of Hong Kong, Hong Kong SAR, China.
9
Department of Cardiovascular and Thoracic Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
10
Institute of Molecular and Cellular Biology, Biopolis, Singapore.
11
Organ Transplantation Institute of Xiamen University, Xiamen, Fujian Province, China. oti@xmu.edu.cn.
12
Department of Medicine, The University of Hong Kong, Hong Kong SAR, China. hftse@hku.hk.
13
Department of Medicine, The University of Hong Kong, Hong Kong SAR, China. qzlian@hku.hk.
14
Peking University Shenzhen Hospital, Shenzhen, China. qzlian@hku.hk.
15
School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China. qzlian@hku.hk.

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.

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