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Download from the Gene (Carl Zeiss, Oberkochen, Germany) BIOCELL Tech Science Press 2021 45(1): 27-39 Basing on microRNA-mRNA analysis identifies microRNA in exosomes associated with wound repair of diabetic ulcers PENG LIU1,2;ANFANG ZOU3;QI CHEN4;BIAO CHENG1,*;QIN LI1,* 1 Department of Burn & Plastic Surgery, General Hospital of Southern Theatre Command of PLA, Guangzhou, 510010, China 2 Huabo Post-Doctoral Research Center, Biological Pharmaceutical Research Institute, Guangzhou, 510515, China 3 Department of Plastic and Cosmetic Surgery, The First Clinical Medical College of Southern Medical University, Guangzhou, 510080, China 4 Department of Dermatology, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510120, China Key words: Exosome, Diabetic ulcer, Angiogenesis, Biological analysis, miRNA Abstract: The diabetic ulcer is one of the serious complications of diabetes. In this study, we aimed to establish an exosomal microRNA (miRNA)-targeted messenger RNA (mRNA) regulatory network for screening new biomarkers for diabetic ulcer treatment. For this purpose, exosomes were extracted from bone marrow stem cells (BMSCs) collected from diabetic ulcer patients and healthy adults. The miRNAs in exosomes was detected by high-throughput sequencing analysis. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the differential miRNAs were performed. The miRNA-mRNA regulatory network between candidate miRNAs and their target genes were constructed by Cytoscape software basing on mRNA expression profiles data of diabetic ulcer patients from Gene Expression Omnibus (GEO). GO and KEGG analyses of the core genes were performed. A total of 63 differential expressed miRNAs in BMSCs exosomes were identified between diabetic ulcer patients and healthy adults. The GO analysis of miRNAs showed that it was mainly related to signal transduction and intercellular transport, and KEGG analysis showed that it was related to the vascular endothelial growth factor (VEGF) signaling pathway. The core genes of the miRNA-mRNA network were thioredoxin interacting protein (TXNIP), cell division cycle 14A (CDC14A), cache domain containing 1 (CACHD1), interferon-induced protein 44 like (IFI44L), late cornified envelope 1AL (CE1A), leucine-rich repeats and immunoglobulin-like domains 2 (LRIG2), palmdelphin (PALMD) and serine and arginine-rich splicing factor 11 (SRSF11). GO analysis of the core genes was related to platelet-derived growth factor receptor signaling pathway. The KEGG analysis of the core genes was related to the cell cycle and nucleotide-binding oligomerization domain (NOD)-like receptor signaling pathway. A potential miRNA-mRNA regulatory network provides a comprehensive understanding of the molecular mechanisms and promising new targets such as miR-130a-5p, SESN2, LRIG2, and CDC14A for the wound repair of diabetic ulcers. Abbreviations IFI44L: interferon induced protein 44 like LCE1A: late cornified envelope 1A miRNAs: microRNAs LRIG2: leucine rich repeats and immunoglobulin like DM: Diabetes mellitus domains 2 AGEs: advancedglycation end products PALMD: Palmdelphin BMSCs: bone marrow stromal cells SRSF11: serine and arginine rich splicing factor 11 CD63: lysosomal membrane-associated glycoprotein 3 FIH: hypoxia inducible factor inhibitor TXNIP: Thioredoxin interacting protein ECM: extracellular matrix CDC14A: Cell division cycle 14A DDL4: Delta like ligand 4 CACHD1: Cache domain containing 1 FDR: false detection rate 3´UTR: 3´ untranslated region *Address correspondence to: Qin Li, [email protected]; Biao Cheng, VEGF: vascular endothelial growth factor [email protected] ERK: extracellular signal-regulated kinase Received: 06 July 2020; Accepted: 23 September 2020 STAT3: signal transducer and activator of transcription 3 Doi: 10.32604/biocell.2021.012601 www.techscience.com/journal/biocell This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 28 PENG LIU et al. HGF: epatocyte growth factor fibroblasts through the Wnt/β-catenin signal pathway(Hu IGF: insulin-like growth factor et al., 2016). BMSCs exosomes can also activate other NGF: nerve growth factor pathways that play an important role in skin wound healing, SDF-1: tromal cell-derived factor-1 such as AKT serine/threonine kinase (AKT), extracellular AGEs: dvanced glycation end products signal-regulated kinase (ERK), and signal transducer and activator of transcription 3 (STAT3) (Ding et al., 2019), and hESCs: human Embryonic Stem Cells promote hepatocyte growth factor (HGF), insulin-like EMT: epithelial-to-mesenchymal transforming growth factor (IGF), nerve growth factor (NGF) and stromal cell-derived factor-1 (SDF-1) and other growth factors (Cui Introduction et al., 2016; Dai et al., 2019; Umezu et al., 2017). MicroRNA (miRNA) is a non-coding RNA with a length Diabetes mellitus (DM) is a metabolic disorder syndrome of 22-24 nucleotides (Bartel, 2004). It participates in the caused by various pathogenic factors such as genetic factors, regulation of the post-transcriptional expression of genes. obesity, immune dysfunction, microbial infection, toxins, Mature miRNA can bind to the 3´ untranslated region (3´- free radicals, and mental factors (Schmidt, 2018). Nowadays, UTR) of target gene messenger RNA (mRNA), and with the improvement of living standards, lifestyle changes, negatively regulate target genes by degrading mRNA and and social aging, the incidence of diabetes was increasing inhibit protein translation of target genes (Fang and year by year (Schmidt, 2018). The diabetic ulcer was one of Rajewsky, 2011). MiRNAs is an important participant in the the serious complications of DM; the risk of foot ulcers in healing of diabetic ulcers, miRNAs can promote the healing diabetic patients is up to 25% (Al-Rubeaan et al., 2015). A of diabetic ulcers by up-regulating or down-regulating the diabetic foot ulcer is the leading cause of low distal expression of some genes and activating specific signaling amputation (Millington and Ellenzweig, 2005). Delayed or pathways (Jhamb et al., 2016). MiRNA is an important nonunion of wound healing after skin injury is a pressing substance for exosomes to promote angiogenesis. It is problem in clinical practice. Some studies have shown that found that miR-31 can promote the proliferation and the accumulation of advanced glycation end products migration of endothelial cells and endothelial progenitor (AGEs) and hyperglycemia will not only damage peripheral cells and induce angiogenesis by inhibiting hypoxia- blood vessels and microvessels but also inhibit the inducible factor inhibitor (FIH) (Liu et al., 2010), miR- expression of many kinds of neurotrophic factors and 125a can inhibit the expression of Delta-like ligand 4 vascular factors, which may be the main factors that cause (DDL4), and promotes endothelial cell formation (Liang et diabetic skin ulcers difficult to heal (Bukowiecki et al., 2017; al., 2016). Exosomes of mesenchymal stem cells (MSCs) Lalla et al., 2000; Negre-Salvayre et al., 2009; Sun et al., 2016). overexpressing miR126 can promote angiogenesis in the A variety of physiological or pathophysiological events such diabetic wound model (Zgheib et al., 2013). as the decreased proliferation of fibroblasts, decreased growth In this study, we used high throughput sequencing of factors, reduced keratinocytes, reduced angiogenesis, mRNA to analyze the difference in MSCs exosomal abnormal collagen deposition, a small number of miRNAs expression between diabetic ulcer patients and macrophages, and impaired function, are related to poor healthy adults. We constructed a miRNA-mRNA network wound healing in DM (Bukowiecki et al., 2017). and analyzed the core genes in the network by Exosomes are extracellular vesicles with a diameter of bioinformatics analysis methods, which aimed to discover 30–150 nm; they have a small bilayer lipid membrane, key targets related to wound healing. which can enter the extracellular matrix directly by budding and then release the internal components after being Materials and Methods ingested by the target cells to complete cell communication and information exchange (Pegtel and Gould, 2019). Patients Exosomes as a subcellular component secreted by cells, The BMSCs were obtained from 5 male patients with diabetic which were widely involved in cell communication and can foot ulcers and 5 male healthy adults in the General Hospital play a dominant role in tissue repair and regeneration of Southern Theatre Command of the Chinese People’s (Chen et al., 2017; Han et al., 2016). They can be identified Liberation Army (PLA) between 2018 JAN to 2019 JAN. by their expression of exosome-associated markers such as The age of patients is 58 ± 10.5 years old, and the duration Tsg101 and CD63 (Wubbolts et al., 2003). In recent years, of DM is 8.5 ± 3.1 years. The age of healthy adults (57 ± 6.2 there are many reports on the application of mesenchymal years old) was matched with diabetic ulcer patients. stem cell-derived exosomes in the treatment of diabetic Informed consent was obtained from all subjects. Inclusion ulcers (Geiger et al., 2015; Zhu et al., 2018). It has been criteria: refer to the World Health Organization (WHO) found that the bone marrow stromal cells (BMSCs) diagnostic criteria for DM. Exclusion criteria: Severe exosomes can promote the proliferation and migration of purulent infections
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