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

Yue Ding; Xiaoting Liang; Yuelin Zhang; Li Yi; Ho Cheung Shum; Qiulan Chen; Barbara P Chan; Huimin Fan; Zhongmin Liu; Vinay Tergaonkar; Zhongquan Qi; Hung-Fat Tse; Qizhou Lian

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

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

Authors

Yue Ding^{1

2

3}, Xiaoting Liang^{2

4

5}, Yuelin Zhang^{2

6}, Li Yi⁷, Ho Cheung Shum⁸, Qiulan Chen⁸, Barbara P Chan⁸, Huimin Fan⁹, Zhongmin Liu^{4

9}, Vinay Tergaonkar¹⁰, Zhongquan Qi¹¹, Hung-Fat Tse¹², Qizhou Lian^{13

14

15}

Affiliations

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. [email protected].
¹² Department of Medicine, The University of Hong Kong, Hong Kong SAR, China. [email protected].
¹³ Department of Medicine, The University of Hong Kong, Hong Kong SAR, China. [email protected].
¹⁴ Peking University Shenzhen Hospital, Shenzhen, China. [email protected].
¹⁵ School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allografts
Animals
Blotting, Western
Cell Proliferation / physiology
Cells, Cultured
Graft Rejection / metabolism*
Heart Transplantation / adverse effects*
Mesenchymal Stem Cells / metabolism*
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
NF-kappa B / metabolism
rap1 GTP-Binding Proteins / deficiency
rap1 GTP-Binding Proteins / genetics
rap1 GTP-Binding Proteins / metabolism*

Substances

NF-kappa B
rap1 GTP-Binding Proteins