Circulating miRNA‐150‐5p is associated with immune‐mediated early β‐cell loss in a humanized mouse model

Abstract

Background Aberrant microRNA (miRNA) expression levels are associated with various graft rejections. We used our humanized mouse model with transplanted human islets to identify miRNAs in islet grafts related to xenograft rejection and circulating miRNAs associated with xenograft rejection‐mediated β‐cell loss. Methods Diabetic immunodeficient NOD.scid mice were transplanted with human islets and subsequently achieved stable normoglycemia. Lymphocytes from NOD mice were then adoptively transferred to the humanized mice to induce human β‐cell destruction. Islet graft and plasma were collected immediately once blood glucose reached >200 mg/dL. miRNAs in the islet grafts and in the plasma with or without adoptive lymphocyte transfer (ALT) were measured using NanoString nCounter® miRNA Expression Assay and qPCR. Results A set of immune‐related miRNAs was significantly increased in human islet grafts of ALT‐treated mice compared to control mice. Of these miRNAs, miR‐150‐5p was significantly increased in the circulation of ALT‐treated mice at tissue collection and the increase was a result of immune activation rather than simply the presence of lymphocytes in circulation. Furthermore, miR‐150‐5p was significantly increased in human islet graft and circulation prior to the development of hyperglycemia in the ALT‐treated mice. Conclusions Our data demonstrated that immune‐related miRNAs are associated with human islet xenograft rejection in mice. miR‐150‐5p is increased in human islet graft and in the circulation during islet xenograft rejection and β‐cell destruction prior to hyperglycemia and may be an early biomarker for islet xenograft rejection.

Plasma miR-150-5p in Renal Transplant Recipients with Acute Antibody-Mediated Rejection

“…This premise could explain the differences between our study and what has previously been reported, whereby patients with ABMR have increased serum miR-150-5p levels but decreased intracellular ones as a result of CD4+ cell activation. Our finding is compatible with what has been reported in murine pancreatic transplantation models, for which an elevation of plasma miR-150-5p has been documented, associated with in-graft rejection and β-cell destruction [25].…”

MicroRNA Expression Changes in Kidney Transplant: Diagnostic Efficacy of miR-150-5p as Potential Rejection Biomarker, Pilot Study

“…This is compatible with our observations, where the activation of CD4+ cells could be associated with the decrease in miR-150-5p. Although serum levels have not been measured in our work, in murine pancreatic transplant models, an elevation of plasma miR-150-5p was associated with graft rejection and destruction of β cells [50].…”

Xenotransplantation literature update, March/April 2019

“…Roat el al attempt to identify microRNAs that could serve as a marker for human β‐cell death through transplanting human islets into a humanized immunodeficient NOD.SCID mouse model followed by adoptively transferred lymphocytes (ATL) from diabetic NOD mice to trigger immune‐induced human β‐cell destruction. Diabetic NOD.SCID mice were found to be normoglycemic following human islet transplantation.…”