Time-course full profiling of circulating miRNAs in neurologically deceased organ donors: a proof of concept study to understand the onset of the cytokine storm

ABSTRACT

Neurologically deceased organ donors (NDDs) generally display an immune response involving an intense production of pro-inflammatory cytokines referred to as the cytokine storm. The sudden surge of inflammatory mediators in circulation promotes tissue and organ damages and ultimately leads to poor transplant outcome. As microRNAs (miRNAs) are frequently proposed as key regulators of inflammation and are relatively stable in circulation, changes in their profiles could play a role in the onset of the cytokine storm in NDDs. In this proof-of-concept study, we sought to investigate differentially abundant circulating miRNAs in a temporal manner between neurological death and organ recovery and to assess the association between specific miRNAs and levels of inflammatory cytokines in blood. Plasma samples from five NDDs were obtained at multiple time points between organ donation consent and organ recovery. Using a time-course analysis and miRNA sequencing, we identified 32 plasma miRNAs fluctuating between consent and organ recovery (false discovery rate; q-value < 0.1). Eleven miRNAs relatively abundant (>100 reads) and detected in all samples were selected for further biological pathway analysis (miR-486-3p, miR-103a-3p, miR-106b-3p, miR-182-5p, miR-101-3p, miR-10a-5p, miR-125a-5p, miR-146b-5p, miR-26a-5p, miR-423-5p, miR-92b-3p). These miRNAs targeted genes such as c-JUN (TNF signalling pathway) and eEF2 (AMPK pathway), suggesting a potential role in regulation of inflammation. Our results contribute to a better understanding of the miRNAs dynamic after neurological death in organ donors and could potentially be used to predict the related early cytokine storm.Trial registration: ClinicalTrials.gov ID NCT03786991. Registered December 2018

KEYWORDS:

• Organ donation
• transplantation
• circulating miRNAs
• microRNAs
• next-generation sequencing
• microtranscriptome

Authors’ contributions

Conception and design of the study: AAC, DL, MCB, LHT, LB, MHM, FDA. Acquisition of data: AAC, DL, CL, MHM. Analysis and interpretation of the data: AAC, DL, MCB, LHT, LFD, LB, FDA. Drafting of the manuscript: AAC, DL, MCB, LB, FDA. Final approval of the article: All authors.

Acknowledgments

Authors would like to thank all members of Pr. Bouchard’s laboratory for scientific discussions and Ms. Lucie Bouffard for performing the cytokines quantification experiments. Authors much appreciated the support of Calcul Québec and Compute Canada for performing the computations on the heterogenous cluster Mammouth-Mp2 (Université de Sherbrooke). Authors sincerely want to acknowledge the donor’ families for their support to this project and thank the ICU staff and research coordinators for samples procurement.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data Availability Statement

The datasets from the current study are available from the corresponding author upon reasonable request.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15592294.2022.2076048

Additional information

Funding

The EPI-STORM study is funded by the Social Sciences and Humanities Research Councils, New Frontiers in Research Funds – Exploration program – NFRFE-2018-02115, by the Projet Structurant du Centre de recherche du Centre hospitalier universitaire de Sherbrooke (CR-CHUS) (grant #91314) and by the Fonds de Recherche du Québec – Santé (FRQ-S) (grant #36786). The granting agency was not involved in any part of the study. A-A.C. and CL were supported by a doctoral award formation from the Fonds de Recherche du Québec - Santé (FRQ-S). LB and FD are respectively senior and junior research scholars from the FRQ-S.