Injury factors alter miRNAs profiles of exosomes derived from islets and circulation.

Qi Fu,Zibin Wang,Tao Yang,Heng Chen,Lei Xiao,Xirong Guo,Hemin Jiang,Xingyun Wang,Ziyang Shen

doi:10.18632/aging.101689

Qi Fu, Zibin Wang + Show 7 more

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https://doi.org/10.18632/aging.101689

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Abstract

Islets damage is a major abnormality underling diabetes. Recent studies suggested the value of exosomes in diagnosis. This study aimed to investigate the impact of injury factors on the miRNA profiles of islet exosomes and determine whether circulating exosomal miRNAs is suitable as biomarkers of islets damage. Islets were isolated from ICR mice and induced injury in vitro by mixed cytokines (Tumor Necrosis Factor-α, Interleukin -1β and Interferon-γ) or streptozotocin (STZ), and exosomes were derived from the cultural supernatant. Using miRNA microarray analysis, we found 22 and 11 differentially expressed miRNAs in islet exosomes of STZ and cytokines treatment, respectively, including 6 miRNAs as the intersection of two injured conditions. Thereinto, mmu-miR-375-3p and mmu-miR-129-5p could be validated by qRT-PCR. Then, Serum exosomes were isolated from STZ injected mice and subjects with various glucose metabolism states and diabetic duration. qRT-PCR demonstrated exosomal mmu-miR-375-3p dramatically increased in serum of STZ treated mouse prior to the disturbance of blood glucose and insulin. In human serum exosomes, hsa-miR-375-3p was elevated in new-onset diabetes patients. Overall, our results suggest that injury factors changed miRNA profiles of exosomes derived from islets and exosomal miR-375-3p showed promising potential as a biomarker of islets damage.

Highlights

Pancreatic islets destruction and cell death is major pathophysiologic abnormalities underling both type 1 diabetes (T1DM) and type 2 diabetes (T2DM), and absolute or relative defects of β cell insulin secretion are characterized by almost all forms of diabetes [1]
After 24 hours incubation, islets of control group showed normal morphology and reasonable viability, whereas STZ and cytokines led to cell death and islets disintegration showed in acridine orange/propidium iodide (AO/PI) staining (Figure 1A)
To detect and monitor islets injury, several groups have evaluated the profiles of free nucleic acids and protein from plasma or bodily fluids as biomarker

Summary

Introduction

Pancreatic islets destruction and cell death is major pathophysiologic abnormalities underling both type 1 diabetes (T1DM) and type 2 diabetes (T2DM), and absolute or relative defects of β cell insulin secretion are characterized by almost all forms of diabetes [1]. Exosomes as one sort of extracellular vesicles (EVs) are secreted into extracellular space by most cell types and found in many bodily fluids. Exosomes are composed of a lipid bilayer and contained soluble and membranebound protein, genomic DNA, RNA (such as mRNA, miRNAs, and other small RNAs), lipids and metabolites derived from the parent cells [3, 4]. By virtue of their www.aging‐us.com various cargoes, exosomes are recognized as essential conveyers of cellular information and participate pleiotropic effects and biological functions in multicellular organisms [5,6,7]. Overwhelming evidences demonstrated that exosomes could accomplish miRNA processing outside mammalian cells [10, 11]

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