Purpose: Pancreatic islets release noncoding microRNAs (miRNAs) upon damage and stress during islet transplant procedures. In this study, we sought to identify miRNAs released by exosomes from human islets exposed to stress conditions during islet transplantation.

Methods: Purified human islets were subjected to hypoxia, cytokine cocktail or both for 24 hrs. Islet exosomes were isolated and miRNAs were sequenced using Illumina NextSeq. Differentially induced exosomal miRNAs expressed in stressed islets were confirmed in vitro by QPCR analysis. Detection of islet-selective exosomal miRNAs in blood sera were further validated in both mouse islet transplant model and clinical transplants. Islet-stress exosomal miRNA were correlated with 1 year post transplant outcomes.

Results: Global miRNA sequencing revealed 879 miRNA species expressed in exosomes from intact human islets. Twenty-four of the miRNAs were highly enriched in exosomes released by islets in response to proinflammatory cytokines, hypoxic stress, or both. Among this group, five miRNAs including 92a-3p, 200c-3p, 29b-3p, 216a-5p and 148a-3p were differentially expressed in circulating exosomes recovered after human islet to mouse xenotransplantation. Whereas hypoxia-induced miRNAs 92a-3p, 216a-3p and 200c-3p were detected exclusively in exosomes released during human islet to mouse kidney capsule transplants, miRNAs 29b-3p and 148a-3p were identified in circulating human islet exosomes recovered from both mouse kidney and intraportal islet transplant models. MiRNA- 216a-3p, 148a, 29b-3p were further identified in exosomes isolated from the sera of patients undergoing islet autotransplantation. High exosomal expression of these islet miRNAs correlated with increased islet cell damage marker miRNA-375 and poor 1-year clinical post-transplant outcomes.

Conclusion: Overall, the results identify novel exosomal miRNAs that are released by islets in a stress-specific manner that can be used as islet stress biomarkers preceding islet cell damage and loss of islet function. These findings may have clinical implications in monitoring stressed islets for interventions during islet transplantation and in the progression of diabetes.

CITATION INFORMATION: Saravanan P., Nguyen P., Yoshimatsu G., Chang C., Darden C., Bhattacharjee R., Wang X., Gu J., Lawrence M., Naziruddin B. Stress-Related Exosomal MicroRNA Biomarkers Released by Human Islets during Transplantation Am J Transplant. 2017;17 (suppl 3).

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