Theranostics 2022; 12(14):6242-6257. doi:10.7150/thno.75543 This issue

Research Paper

Single-Cell RNA sequencing reveals immune cell dynamics and local intercellular communication in acute murine cardiac allograft rejection

Zhang Chen1,2#, Heng Xu1#, Yuan Li1,2#, Xi Zhang1, Jikai Cui1,2, Yanqiang Zou1, Jizhang Yu1,2✉, Jie Wu1,2✉, Jiahong Xia1,2✉

1. Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
2. Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
#These authors contributed equally to this work.

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Citation:
Chen Z, Xu H, Li Y, Zhang X, Cui J, Zou Y, Yu J, Wu J, Xia J. Single-Cell RNA sequencing reveals immune cell dynamics and local intercellular communication in acute murine cardiac allograft rejection. Theranostics 2022; 12(14):6242-6257. doi:10.7150/thno.75543. Available from https://www.thno.org/v12p6242.htm

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Abstract

Graphic abstract

Rationale: Transplant rejection is a major impediment to long-term allograft survival, in which the actions of immune cells are of fundamental importance. However, the immune cell dynamics and local intercellular communication of acute cardiac allograft rejection are not completely clear.

Methods: Here we performed single-cell RNA sequencing on CD45+ immune cells isolated from cardiac grafts and spleens in a model of murine heterotopic heart transplantation. Moreover, we applied unsupervised clustering, functional enrichment analysis, cell trajectory construction and intercellular communication analysis to explore the immune cell dynamics and local intercellular communication of acute cardiac allograft rejection at single-cell level. The effect of CXCR3 antagonist and neutralizing antibody against its ligand on allograft rejection and T cell function was evaluated in murine heart transplantation model.

Results: We presented the immune cell landscape of acute murine cardiac allograft rejection at single-cell resolution, and uncovered the functional characteristics and differentiation trajectory of several alloreactive cell subpopulations, including Mki67hi CTLs, Ccl5hi CTLs, activated Tregs and alloreactive B cells. We demonstrated local intercellular communication and revealed the upregulation of CXCR3 and its ligands in cardiac allografts. Finally, CXCR3 blockade significantly suppressed acute cardiac allograft rejection and inhibited the alloreactive T cell function.

Conclusions: These results provide a new insight into the immune cell dynamics and local intercellular communication of acute cardiac allograft rejection, and suggest CXCR3 pathway may serve as a potential therapeutic target for transplant rejection.

Keywords: Single-cell RNA transcriptomics, Acute rejection, Murine heart transplantation, Immune landscape, Intercellular communication