Human urine-derived stem cell-derived exosomal miR-21-5p promotes neurogenesis to attenuate Rett syndrome via the EPha4/TEK axis

• Published in: Laboratory investigation Vol. 101; no. 7; pp. 824 - 836
• Main Authors: Pan, Wei, Xu, Xiaoheng, Zhang, Meng, Song, Xingyu
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.07.2021; Nature Publishing Group US; Nature Publishing Group
• Subjects: 13/100; 13/51; 692/699/375; 692/699/375/2764; Adult; Animals; Behavior, Animal - drug effects; Cognition - drug effects; Cognitive ability; Differentiation; Disabilities; Doublecortin Protein; EphA4 protein; Exosomes; Exosomes - chemistry; Flow cytometry; Fluorescent dyes; Fluorescent indicators; Human wastes; Humans; Ischemia; Laboratory Medicine; Medicine; Medicine & Public Health; Mice; MicroRNAs - pharmacology; miRNA; Neurodevelopmental disorders; Neurogenesis; Neurogenesis - drug effects; Pathology; Receptor, EphA4 - genetics; Receptor, EphA4 - metabolism; Receptor, TIE-2 - genetics; Receptor, TIE-2 - metabolism; Recovery of function; Rett syndrome; Rett Syndrome - metabolism; Ribonucleic acid; RNA; Stem cell transplantation; Stem cells; Stem Cells - chemistry; Subventricular zone; Transcription; Transmission electron microscopy; Tubulin; Urine; Urine - cytology; Ventricle; Ventricles (cerebral); Western blotting
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/s41374-021-00574-w

Rett syndrome (RTT) is a rare neurodevelopmental disorder that results in multiple disabilities. Exosomal microRNA (miRs) from urine-derived stem cells (USCs) have been shown to induce neurogenesis and aid in functional recovery from brain ischemia. In the present study, we sought to determine whether that exosomal miR-21-5p from USCs could promote early neural formation in a model of RTT. USCs were isolated and evaluated by flow cytometry. Exosomes were analyzed by transmission electron microscopy, tunable resistive pulse sensing (TRPS), and western blotting. PKH26 fluorescent dyes were used to observe intake of exosomes in vivo and in vitro. An RTT mouse model was treated with exosomes for behavioral studies. Dual‐luciferase report gene assays were conducted to evaluate the relationship between miR-21-5p and Eph receptor A4 (EphA4). In vitro, treatment with exosomes from human urine‐derived stem cells (USC-Exos) increased the percentage of neuron-specific class III beta-tubulin (Tuj1)+ nerve cells as well as the transcription levels of β-III tubulin and doublecortin (DCX). A higher level of miR-21-5p was observed in USC-Exos, which promoted differentiation in NSCs by targeting the EPha4/TEK axis. In vivo, exosomal miR-21-5p improved the behavior, motor coordination, and cognitive ability of mice, facilitated the differentiation of NSCs in the subventricular zone of the lateral ventricle and promoted a marked rise in the number of DCX+ cells. Our data provide evidence that exosomal miR-21-5p from human USCs facilitate early nerve formation by regulating the EPha4/TEK axis. Rett syndrome (RTT) is a rare neurodevelopmental disorder that results in severe multiple disabilities. This study provides evidence that exosomal miR-21-5p from human urine-derived stem cells facilitates early neural formation by regulating the EPha4/TEK axis, and may be a promising therapeutic option for this devastating disease.