Exosomes from mmu_circ_0001052-modified adipose-derived stem cells promote angiogenesis of DFU via miR-106a-5p and FGF4/p38MAPK pathway

Abstract

Background Diabetic foot ulcer (DFU) is a chronic infectious disease caused by diabetes mellitus (DM). Angiogenesis plays the decisive role in wound healing of DFU. Adipose-derived stem cells (ADSCs) can ameliorate angiogenesis in DFU by exosomes. This study aims to determine the mechanism of exosomes from mmu_circ_0001052-modified ADSCs in angiogenesis of DFU. Methods HUVECs were induced by high glucose and mice stimulated using STZ injection during high-fat feeding, which were treated with exosomes derived from mmu_circ_0001052-modified ADSCs. Real-time PCR determined the expression of gene and western blot determined protein levels. Proliferation, migration, apoptosis and angiogenesis of HUVECs were studied by MTT assay, transwell test, flow cytometry and tube formation experiment, respectively. Histological lesion of wound was determined by HE staining. Results The expression of circ_0001052 was upregulated in ADSCs and miR-106a-5p elevated in high glucose-induced HUVECs. Exosomal mmu_circ_0001052 significantly accelerated wound healing in mice with DFU. Also, exosomal mmu_circ_0001052 evoked the reduction of miR-106a-5p and the elevation of FGF4 in high glucose-induced HUVECs and wound tissue of DFU mice. Exosomal mmu_circ_0001052 was determined to sponge miR-106a-5p that targeted FGF4 in DFU. In high glucose-induced HUVECs, exosomal mmu_circ_0001052 inhibited apoptosis and miR-106a-5p expression, and meanwhile promoted proliferation, migration, angiogenesis and expressions of FGF4, VEGF and p-p38/p38, which were reversed by miR-106a-5p elevation. Conclusion Mmu_circ_0001052 in ADSCs-derived exosomes promote angiogenesis of DFU via miR-106a-5p and FGF4/p38MAPK pathway. Graphical Abstract

Effects of Intensive Glycemic Control on Serum Exosome miR‐126‐3p and miR‐125b‐1‐3p Levels and Wound Healing in Patients with Diabetic Ulcers

“…Several studies have confrmed that many miRNAs participate in the process of wound healing [26][27][28][29]. During the infammatory period of the wound, miRNA-181c and miRNA-21-5p promote the expression of M2 macrophages to inhibit the infammatory response and shorten the infammatory response time [30,31].…”

How to maximize the therapeutic effect of exosomes on skin wounds in diabetes mellitus: Review and discussion

“…However, in the diabetic environment, the number and function of these cells are restricted to varying degrees, and the wound-healing process is delayed or interrupted. Studies found that exosomes could greatly promote survival and inhibit the apoptosis of ECs (14)(15)(16)(17), fibroblasts (11), keratocytes (11), and neurons (11). Mostly, exosomes were reported to promote the proliferation, migration, and angiogenesis of endothelial cells, and a variety of pathways were involved, like PI3K/AKT pathway, ERK1/2 pathway, FGF4/p38MAPK pathway and HIPK2 pathway (15,(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29).…”

“…Studies found that exosomes could greatly promote survival and inhibit the apoptosis of ECs (14)(15)(16)(17), fibroblasts (11), keratocytes (11), and neurons (11). Mostly, exosomes were reported to promote the proliferation, migration, and angiogenesis of endothelial cells, and a variety of pathways were involved, like PI3K/AKT pathway, ERK1/2 pathway, FGF4/p38MAPK pathway and HIPK2 pathway (15,(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). This greatly enhances the ability of local vascular regeneration in diabetic wound healing.…”

“…Up to now, exosomes from various cell sources have been used to promote wound healing in diabetes. Stem cells are the most studied, including adipose stem cells (ADSCs) ( 11 , 17 , 28 , 31 , 35 , 38 , 40 – 47 ), bone marrow mesenchymal stem cells (BMSCs) ( 15 , 16 , 23 , 26 , 32 , 33 , 37 , 44 , 48 – 51 ), human umbilical cord-derived mesenchymal stem cells (hUCMSCs) ( 27 , 52 , 53 ), synovium mesenchymal stem cells (SMSCs) ( 18 , 21 ), gingival mesenchymal stem cells (GMSCs) ( 39 ), human urine-derived stem cells (USCs) ( 22 ), menstrual blood-derived mesenchymal stem cells (MenSCs) ( 36 ), placental mesenchymal stem cells (PMSCs) ( 54 ), human endometrial stem cells (hEnSCs) ( 34 ), hair follicle-derived mesenchymal stromal cells ( 55 ), epidermal stem cells (ESCs) ( 56 , 57 ). Other cells, like fibrocytes ( 58 ), human umbilical cord blood endothelial progenitor cells ( 19 , 59 ), human umbilical cord blood mononuclear cells (hUCBMNCs) ( 30 ), macrophages ( 24 ), human amniotic epithelial cells ( 25 ), dermal fibroblasts (DFs) ( 14 ), M2 macrophages ( 60 ), human umbilical vein endothelial cells (HUVECs) ( 61 ), also were used for exosome isolation.…”

Extracellular vesicles derived from fibroblasts induced with or without high glucose exert opposite effects on wound healing and angiogenesis

“…Numerous proangiogenic factors are produced under hypoxia circumstances. These factors, the most notable of which is VEGF, activate the endothelial cells, stimulate capillaries to form nascent immature loops and branches to provide oxygen and nutrients to the wound site ( 1 , 2 ). Communication between fibroblasts and endothelial cells is essential for skin wound repair and regeneration.…”