Melatonin Synergizes With Mesenchymal Stromal Cells Attenuates Chronic Allograft Vasculopathy
Authors: Cheng-Lu Sun
Yi-Ming Zhao
Hong Qin
Hong-da Wang
Jing-Peng Hao
Guang-Ming Li
Ya-Fei Qin
Hao Wang
Yang-Lin Zhu
De-Jun Kong
Journal: Frontiers in Immunology (2021)
Discipline: IMMUNOLOGY
Keywords: aorta transplantation; chronic allograft vasculopathy; melatonin; mesenchymal stromal cells; mice.
Affiliations: Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China., Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China., Department of Anorectal Surgery, The Second Hospital of Tianjin Medical University, Tianjin, China.

Abstract:  Background: Chronic rejection characterized by chronic allograft vasculopathy (CAV) remains a major obstacle to long-term graft survival. Due to multiple complicated mechanisms involved, a novel therapy for CAV remains exploration. Although mesenchymal stromal cells (MSCs) have been ubiquitously applied to various refractory immune-related diseases, rare research makes a thorough inquiry in CAV. Meanwhile, melatonin (MT), a wide spectrum of immunomodulator, plays a non-negligible role in transplantation immunity. Here, we have investigated the synergistic effects of MT in combination with MSCs in attenuation of CAV. Methods: C57BL/6 (B6) mouse recipients receiving BALB/c mouse donor aorta transplantation have been treated with MT and/or adipose-derived MSCs. Graft pathological changes, intragraft immunocyte infiltration, splenic immune cell populations, circulating donor-specific antibodies levels, cytokine profiles were detected on post-operative day 40. The proliferation capacity of CD4+ and CD8+ T cells, populations of Th1, Th17, and Tregs were also assessed in vitro. Results: Grafts in untreated recipients developed a typical pathological feature of CAV characterized by intimal thickening 40 days after transplantation. Compared to untreated and monotherapy groups, MT in combination with MSCs effectively ameliorated pathological changes of aorta grafts indicated by markedly decreased levels of intimal hyperplasia and the infiltration of CD4+ cells, CD8+ cells, and macrophages, but elevated infiltration of Foxp3+ cells. MT either alone or in combination with MSCs effectively inhibited the proliferation of T cells, decreased populations of Th1 and Th17 cells, but increased the proportion of Tregs in vitro. MT synergized with MSCs displayed much fewer splenic populations of CD4+ and CD8+ T cells, Th1 cells, Th17 cells, CD4+ central memory T cells (Tcm), as well as effector memory T cells (Tem) in aorta transplant recipients. In addition, the percentage of splenic Tregs was substantially increased in the combination therapy group. Furthermore, MT combined with MSCs markedly reduced serum levels of circulating allospecific IgG and IgM, as well as decreased the levels of pro-inflammatory IFN-γ, TNF-α, IL-1β, IL-6, IL-17A, and MCP-1, but increased the level of IL-10 in the recipients. Conclusions: These data suggest that MT has synergy with MSCs to markedly attenuate CAV and provide a novel therapeutic strategy to improve the long-term allograft acceptance in transplant recipients. 

Retracted: No

PubPeer comments:
 Dear authors, Figure 3A and Figure 6A contains a duplicates FACS plot, could you please check? Figure 3A ![file] Figure 6A ![file] , 
 **CORRECTION** https: www.frontiersin.org articles 10.3389 fimmu.2021.741234 full A Corrigendum on Melatonin Synergizes with Mesenchymal Stromal Cells Attenuates Chronic Allograft Vasculopathy By Qin YF, Kong DJ, Qin H, Zhu YL, Li GM, Sun CL, Zhao YM, Wang HD, Hao JP, Wang H. Front Immunol. 2021 Apr 29; 12:672849. doi: 10.3389 fimmu.2021.672849. Error in Figure In the original article, there was a mistake in Figure 3A and Figure 6A as published. The figures were placed repeatedly in the process of copying pasting our original images. The corrected Figure 3A and Figure 6A appears below. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated ,