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Published on: October 26, 2017
Plasma microRNA, a potential biomarker for acute rejection after liver transplantation
Jie Hu1, Zheng Wang, Chang-Jun Tan
1Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), the Chinese Ministry of Education, and Shanghai Key Laboratory for Organ Transplantation, Shanghai, PR China.
Background:
Acute rejection (AR) of an organ transplant is a life-threatening complication. Currently, there are few diagnostic biomarkers suitable for clinical application. We aim to determine the potential of plasma microRNAs as biomarkers for AR.
Methods:
Using rat orthotopic liver transplantation model and microarrays, we compared the difference in the spectrum and levels of microRNAs in both plasma and grafts between AR rats and control. AR-related plasma microRNAs were selected and validated using real-time quantification polymerase chain reaction. Plasma from AR rats with or without tacrolimus treatment was used for microRNA dynamic monitoring. To clarify the origin of AR-related plasma microRNAs, drug-induced liver damage rat model were performed and in situ hybridization was used to detect and localize the specific microRNA in allografts.
Results:
We found that plasma miR-122, miR-192, and miR-146a was significantly up-regulated when AR occur (fold change>2; P<0.05) and the elevation could be repressed by immunosuppression. In liver injury rat model, up-regulated plasma miR-122 (fold change=22.126; P=0.002) and miR-192 (fold change=8.833; P<0.001) rather than miR-146a (fold change=1.181; P=0.594) were observed. Further study demonstrated that miR-146a was up-regulated by sixfold in microvesicles isolated from AR plasma, whereas miR-122 and miR-192 showed no distinct change. In situ hybridization revealed that the portal areas of the AR graft were brimming with lymphocytes, which showed highly intense staining for miR-146a.
Conclusions:
Our study provides the global fingerprint of plasma microRNAs in AR rats and suggests that plasma miR-122 and miR-192 reflect liver injury, whereas miR-146a may associate with cellular rejection.
Insights
Plasma microRNAs show promise as biomarkers for acute rejection (AR) after organ transplantation. Specific microRNAs, miR-122 and miR-192, indicate liver injury, while miR-146a may signal cellular rejection.
Area of Science:
- Transplantation immunology
- Molecular diagnostics
- Biomarker discovery
Background:
- Acute rejection (AR) is a critical complication following organ transplantation.
- Current diagnostic biomarkers for AR are limited in clinical utility.
- Plasma microRNAs are being investigated as potential non-invasive biomarkers for AR.
Purpose of the Study:
- To identify and validate plasma microRNAs as biomarkers for acute rejection in organ transplantation.
- To differentiate microRNA signatures associated with liver injury versus cellular rejection.
- To investigate the origin and dynamics of AR-related plasma microRNAs.
Main Methods:
- Utilized a rat orthotopic liver transplantation model to compare plasma and graft microRNA profiles in AR versus control groups.
- Employed microarrays for initial screening and real-time quantitative polymerase chain reaction (qPCR) for validation.
- Conducted dynamic microRNA monitoring in plasma during tacrolimus treatment and used in situ hybridization to localize microRNAs within grafts.
Main Results:
- Plasma miR-122, miR-192, and miR-146a were significantly upregulated during AR and responsive to immunosuppression.
- miR-122 and miR-192 elevations correlated with liver injury in a separate rat model.
- miR-146a was notably enriched in microvesicles from AR plasma and localized to lymphocytes within rejecting allografts, suggesting a role in cellular rejection.
Conclusions:
- Plasma microRNA profiles offer a global fingerprint for assessing AR in organ transplants.
- Plasma miR-122 and miR-192 serve as indicators of liver injury.
- Plasma miR-146a is associated with cellular rejection, potentially originating from infiltrating lymphocytes.
