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Integrative small and long RNA-omics analysis of human healing and non-healing wounds discovers cooperating microRNAs as therapeutic targets

ABSTRACT: Due to microRNAs' (miRs) important functions and high potential for disease diagnosis and therapy, increasing efforts have been put to understand their role in wound repair and identify targetable miRs for wound treatment. However, lack of knowledge about miR-mediated gene expression in human wound tissues hinders the recognition of clinically relevant miRs. Here we profiled genome-wide miR and mRNA expression by RNA-sequencing in the same set of samples from human normal acute wounds and chronic non-healing venous ulcers (VU). By integrative analysis of miR and mRNA omics, we unraveled miR-mediated gene regulatory networks specifically associated with different phases of wound repair or VU. We also identified transcriptional factors and miR arm switching events underpinning the dynamically changed miR expression. In this study, we focused on not only a few top changed miRs, but also the miRs with their targetome enriched in the VU gene signature, such as miR-34a-5p, miR-34c-5p, miR-218-5p, miR-7704, miR-424-5p, miR-450-5p, miR-517b-3p, miR-96-5p, and miR-516b-5p. We confirmed these miRs' targetome in human keratinocytes and fibroblasts using microarrays and demonstrated their functional relevance to VU pathology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE174661 | GEO | 2022/03/06

REPOSITORIES: GEO

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Project description:Lifestyle disorders like obesity, type 2 diabetes (T2D), and cardiovascular diseases can be prevented and treated by regular physical activity. During exercise, skeletal muscles release signaling factors that communicate with other organs and mediate beneficial effects of exercise. These factors include myokines, metabolites, and extracellular vesicles (EVs). In the present study, we have examined how electrical pulse stimulation (EPS) of myotubes, a model of exercise, affects the cargo of released EVs. Chronic low frequency EPS was applied for 24 h to human myotubes isolated and differentiated from biopsy samples from 6 morbidly obese females with T2D, and EVs, both exosomes and microvesicles (MV), were isolated from cell media 24 h thereafter. Size and concentration of EV subtypes were characterized by nanoparticle tracking analysis, surface markers were examined by flow cytometry and Western blotting, and morphology was confirmed by transmission electron microscopy. Protein content was assessed by high-resolution proteomic analysis (LC-MS/MS), non-coding RNA was quantified by Affymetrix microarray, and selected microRNAs (miRs) validated by real time RT-qPCR. The size and concentration of exosomes and MV were unaffected by EPS. Of the 400 miRs identified in the EVs, EPS significantly changed the level of 15 exosome miRs, of which miR-1233-5p showed the highest fold change. The miR pattern of MV was unaffected by EPS. Totally, about 1000 proteins were identified in exosomes and 2000 in MV. EPS changed the content of 73 proteins in exosomes, 97 in MVs, and of these 4 were changed in both exosomes and MV (GANAB, HSPA9, CNDP2, and ATP5B). By matching the EPS-changed miRs and proteins in exosomes, 31 targets were identified, and among these several promising signaling factors. Of particular interest were CNDP2, an enzyme that generates the appetite regulatory metabolite Lac-Phe, and miR-4433b-3p, which targets CNDP2. Several of the regulated miRs, such as miR-92b-5p, miR-320b, and miR-1233-5p might also mediate interesting signaling functions.

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Integrative small and long RNA-omics analysis of human healing and non-healing wounds discovers cooperating microRNAs as therapeutic targets

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