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

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

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

86 Citations (Scopus)

11 Downloads (CityUHK Scholars)

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. © 2018 The Author(s).

Original language	English
Article number	386
Journal	Cell Death and Disease
Volume	9
Issue number	3
DOIs	https://doi.org/10.1038/s41419-018-0414-3
Publication status	Published - 1 Mar 2018
Externally published	Yes

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Publication details (e.g. title, author(s), publication statuses and dates) are captured on an “AS IS” and “AS AVAILABLE” basis at the time of record harvesting from the data source. Suggestions for further amendments or supplementary information can be sent to [email protected].

Funding

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.).

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This full text is made available under CC-BY 4.0. https://creativecommons.org/licenses/by/4.0/

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Ding, Y., Liang, X., Zhang, Y., Yi, L., Shum, H. C., Chen, Q., Chan, B. P., Fan, H., Liu, Z., Tergaonkar, V., Qi, Z., Tse, H.-F., & Lian, Q. (2018). Rap1 deficiency-provoked paracrine dysfunction impairs immunosuppressive potency of mesenchymal stem cells in allograft rejection of heart transplantation. Cell Death and Disease, 9(3), Article 386. https://doi.org/10.1038/s41419-018-0414-3

@article{f7d63374ab294f4faef78e1018584fcc,

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

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. {\textcopyright} 2018 The Author(s).",

author = "Yue Ding and Xiaoting Liang and Yuelin Zhang and Li Yi and Shum, \{Ho Cheung\} and Qiulan Chen and Chan, \{Barbara P.\} and Huimin Fan and Zhongmin Liu and Vinay Tergaonkar and Zhongquan Qi and Hung-Fat Tse and Qizhou Lian",

note = "Publication details (e.g. title, author(s), publication statuses and dates) are captured on an “AS IS” and “AS AVAILABLE” basis at the time of record harvesting from the data source. Suggestions for further amendments or supplementary information can be sent to [email protected].",

year = "2018",

month = mar,

day = "1",

doi = "10.1038/s41419-018-0414-3",

language = "English",

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Ding, Y, Liang, X, Zhang, Y, Yi, L, Shum, HC, Chen, Q, Chan, BP, Fan, H, Liu, Z, Tergaonkar, V, Qi, Z, Tse, H-F & Lian, Q 2018, 'Rap1 deficiency-provoked paracrine dysfunction impairs immunosuppressive potency of mesenchymal stem cells in allograft rejection of heart transplantation', Cell Death and Disease, vol. 9, no. 3, 386. https://doi.org/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, Yue; Liang, Xiaoting; Zhang, Yuelin et al.
In: Cell Death and Disease, Vol. 9, No. 3, 386, 01.03.2018.

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

TY - JOUR

T1 - Rap1 deficiency-provoked paracrine dysfunction impairs immunosuppressive potency of mesenchymal stem cells in allograft rejection of heart transplantation

AU - Ding, Yue

AU - Liang, Xiaoting

AU - Zhang, Yuelin

AU - Yi, Li

AU - Shum, Ho Cheung

AU - Chen, Qiulan

AU - Chan, Barbara P.

AU - Fan, Huimin

AU - Liu, Zhongmin

AU - Tergaonkar, Vinay

AU - Qi, Zhongquan

AU - Tse, Hung-Fat

AU - Lian, Qizhou

N1 - Publication details (e.g. title, author(s), publication statuses and dates) are captured on an “AS IS” and “AS AVAILABLE” basis at the time of record harvesting from the data source. Suggestions for further amendments or supplementary information can be sent to [email protected].

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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. © 2018 The Author(s).

AB - 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. © 2018 The Author(s).

UR - https://www.scopus.com/pages/publications/85048282502

UR - https://www.scopus.com/pages/publications/85048282502#tab=impact

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DO - 10.1038/s41419-018-0414-3

M3 - RGC 21 - Publication in refereed journal

C2 - 29515165

SN - 2041-4889

VL - 9

JO - Cell Death and Disease

JF - Cell Death and Disease

IS - 3

M1 - 386

ER -

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

Abstract

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