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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: We identified pathologically relevant miRs that exhibited abnormal VU expression and displayed their targets enriched explicitly in the VU gene signature. The biological function of these miRNAs in human epidermal keratinocytes or fibroblasts during wound repair remains unclear. To study the genes regulated by miR-96-5p, miR-218-5p, miR-424-5p, miR-450b-5p, miR-516b-5p or miR-7704, we transfected miRNA mimics into human primary epidermal keratinocytes or fibroblasts to overexpress respective miRNA expression. We performed a global transcriptome analysis of keratinocytes or fibroblasts upon miRNA overexpression using Affymetrix arrays.

ORGANISM(S): Homo sapiens

PROVIDER: GSE196773 | GEO | 2022/02/16

REPOSITORIES: GEO

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Project description:Diabetic foot ulcers (DFUs) are one of the major complications of diabetes. Its molecular pathology remains poorly understood, impeding the development of effective treatments. Although it has been established that multiple cell types, including fibroblasts, keratinocytes, macrophages and endothelial cells, all contribute to inhibition of healing, less is known regarding individual contributions of each cell type. Thus, we generated primary fibroblasts from non-healing DFUs and evaluated their cellular and molecular properties in comparison to non-diabetic foot fibroblasts (NFFs). Specifically, we analyzed both micro-RNA and mRNA expression profiles of primary DFU fibroblasts. These paired genomic analyses identified a total of 331 reciprocal miRNA-mRNA pairs (21 miRNAs (FC>2.0) along with 239 predicted target genes (FC>1.5) that are significantly and differentially expressed. Of these, we focused on three miRNAs (miR-21-5p, miR-34a-5p, miR-145-5p) found to be induced in DFU fibroblasts as most differentially regulated. Their involvement in cellular functions important for wound healing was investigated by testing the expression of their downstream targets as well as by quantifying cellular behaviors in a prospectively collected and generated cell lines from 15 patients (7 DFUF and 8 NFF samples). We found large number of downstream targets of miR-21-5p, miR-34a-5p, miR-145-5p to be coordinately regulated in mRNA profiles, which was confirmed by qPCR. Genomic analysis of miR-21-5p, miR-34a-5p, miR-145-5p and their target genes indicates that these are contributing to the inhibition of cell movement and cell proliferation, together with increased cell differentiation and senescence in DFU fibroblasts, which was confirmed by cellular assays. We conclude that induction of miR-21-5p, miR-34a-5p, miR-145-5p in DFU dermal fibroblasts plays an important role in impairing multiple cellular functions, thus contributing to overall inhibition of healing in DFUs.

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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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