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Preventing alloimmune rejection using circular RNA FSCN1-silenced dendritic cells in heart transplantation.
Wang, Bowen; Zhou, Qinfeng; Li, Toni; Li, Shuailong; Greasley, Adam; Skaro, Anton; Quan, Douglas; Min, Weiping; Liu, Kexiang; Zheng, Xiufen.
Affiliation
  • Wang B; Department of Cardiovascular Surgery, The Second Affiliated Hospital, Jilin University, Changchun, China; Department of Pathology and Laboratory Medicine, Western University, London, Ontario Canada.
  • Zhou Q; Department of Surgery, Western University, London, Ontario Canada.
  • Li T; Department of Pathology and Laboratory Medicine, Western University, London, Ontario Canada; School of Medicine, Queen's University, Kingston, Canada.
  • Li S; Department of Cardiovascular Surgery, The Second Affiliated Hospital, Jilin University, Changchun, China; Department of Pathology and Laboratory Medicine, Western University, London, Ontario Canada.
  • Greasley A; Department of Pathology and Laboratory Medicine, Western University, London, Ontario Canada.
  • Skaro A; Department of Surgery, Western University, London, Ontario Canada.
  • Quan D; Department of Surgery, Western University, London, Ontario Canada.
  • Min W; Department of Pathology and Laboratory Medicine, Western University, London, Ontario Canada; Department of Surgery, Western University, London, Ontario Canada; Lawson Health Research Institute, London, Ontario Canada; Department of Oncology, Western University, London, Ontario Canada.
  • Liu K; Department of Cardiovascular Surgery, The Second Affiliated Hospital, Jilin University, Changchun, China.
  • Zheng X; Department of Pathology and Laboratory Medicine, Western University, London, Ontario Canada; Department of Surgery, Western University, London, Ontario Canada; Lawson Health Research Institute, London, Ontario Canada; Department of Oncology, Western University, London, Ontario Canada. Electronic add
J Heart Lung Transplant ; 40(7): 584-594, 2021 07.
Article in En | MEDLINE | ID: mdl-34052126
ABSTRACT

BACKGROUND:

While heart transplantation is used as a standard treatment for heart failure, transplant rejection continues to pose a challenge. Recent evidence has shown that circular RNA (circRNA) is a new type of gene regulator in cell development. Our aim was to demonstrate that treatment with tolerogenic dendritic cells (Tol-DCs) generated by circular RNA FSCN1 (circFSCN1) silencing could prevent alloimmune rejection and prolong heart graft survival in heart transplantation.

METHODS:

Bone marrow-derived DCs were transfected with circFSCN1 siRNA in vitro. The circFSCN1 level was measured by qRT-PCR. DC maturation was determined by flow cytometry. Mixed lymphocyte reactions (MLRs) were conducted to assess the function of DCs to activate T cells and to generate regulatory T cells (Tregs). In situ RNA hybridization and fluorescent microscopy were performed to detect the distribution of circFSCN1 in DCs. A heterotopic allogeneic murine heart transplantation was conducted where recipients were pre-treated with donor derived circFSCN1-silenced Tol-DCs. Heartbeat was monitored to assess immune rejection.

RESULTS:

Exonic circFSCN1 was highly expressed in the cytoplasm of mature DCs. Knockdown of circFSCN1 using siRNA arrested DCs at an immature state, impaired DC's ability to activate T cells and enhanced Treg generation. Treatment with circFSCN1-silenced Tol-DCs prevented alloimmune rejection, prolonged allograft survival, reduced fibrosis, and induced Tregs in vivo.

CONCLUSIONS:

Knockdown of circFSCN1 induces Tol-DCs and treatment with these Tol-DCs prevents alloimmune rejection and prolongs allograft survival. This is a promising therapeutic target to combat transplant rejection in heart transplantation and increases our understanding of circRNA in the immune system.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Dendritic Cells / Gene Expression Regulation / Heart Transplantation / Receptors, Odorant / RNA, Circular / Graft Rejection / Immune Tolerance / Microfilament Proteins Limits: Animals Language: En Journal: J Heart Lung Transplant Journal subject: CARDIOLOGIA / TRANSPLANTE Year: 2021 Document type: Article
Fulltext
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Print
XML
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Dendritic Cells / Gene Expression Regulation / Heart Transplantation / Receptors, Odorant / RNA, Circular / Graft Rejection / Immune Tolerance / Microfilament Proteins Limits: Animals Language: En Journal: J Heart Lung Transplant Journal subject: CARDIOLOGIA / TRANSPLANTE Year: 2021 Document type: Article