Circulating Exosomal miR‐20b‐5p Inhibition Restores Wnt9b Signaling and Reverses Diabetes‐Associated Impaired Wound Healing

Abstract

At present, developing therapeutic strategies to improve wound healing in individuals with diabetes remains challenging. Exosomes represent a promising nanomaterial from which microRNAs (miRNAs) can be isolated. These miRNAs have the potential to exert therapeutic effects, and thus, determining the potential therapeutic contributions of specific miRNAs circulating in exosomes is of great importance. In the present study, circulating exosomal miRNAs are identified in diabetic patients and assessed for their roles in the context of diabetic wound healing. A significant upregulation of miR‐20b‐5p is observed in exosomes isolated from patients with type 2 diabetes mellitus (T2DM), and this miRNA is able to suppress human umbilical vein endothelial cell angiogenesis via regulation of Wnt9b/β‐catenin signaling. It is found that the application of either miR‐20b‐5p or diabetic exosomes to wound sites is sufficient to slow wound healing and angiogenesis. In diabetic mice, it is found that knocking out miR‐20b‐5p significantly enhances wound healing and promotes wound angiogenesis. Together, these findings thus provide strong evidence that miR‐20b‐5p is highly enriched in exosomes from patients with T2DM and can be transferred to cells of the vascular endothelium, where it targets Wnt9b signaling to negatively regulate cell functionality and angiogenesis.

Substantially Altered Expression Profile of Diabetes/Cardiovascular/Cerebrovascular Disease Associated microRNAs in Children Descending from Pregnancy Complicated by Gestational Diabetes Mellitus—One of Several Possible Reasons for an Increased Cardiovascular Risk

“…The hypothesis of the assessment of potential diabetes/cardiovascular risk in children prenatally exposed to GDM was based on the knowledge that a serious of microRNAs play a role in the pathogenesis of diabetes mellitus and cardiovascular/cerebrovascular diseases ( Table 1 ) [ 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , <...>…”

“…Previously, by searching the Medline database we identified a large scale of microRNAs playing a role in pathogenesis of diabetes mellitus and cardiovascular/cerebrovascular diseases. Finally, we selected for the study a shortlist of 29 microRNAs demonstrated repetitively by numerous scientific teams to be associated with normal stages (development and homeostasis of the cardiovascular system, angiogenesis, and adipogenesis) and pathological conditions and diseases (vascular endothelial dysfunction and inflammation, hypoxia, hypertension and regulation of hypertension-related genes, obesity, dyslipidaemia, atherosclerosis and atherosclerotic plaque formation, insulin resistance, diabetes mellitus and diabetes-related complications, metabolic syndrome, cardiovascular diseases involving the blood vessels (coronary and peripheral artery diseases, carotid artery disease, pulmonary arterial hypertension, cerebrovascular disease, aortic and intracranial aneurysms), cardiovascular diseases involving the heart (congenital heart disease, cardiomyopathies, cardiac dysrhythmias, hypertensive heart disease, myocardial disease, valvular heart disease, inflammatory heart disease, rheumatic heart disease, pulmonary heart disease, and heart failure), chronic kidney disease, ischemia/reperfusion injury, cardiac regeneration and cachexia) ( Table 1 ) [ 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ,…”

Mechanistic Actions of microRNAs in Diabetic Wound Healing

“…Slow wound healing mediated by high levels of exosomal miR-20b, was observed in vivo and in vitro when exosomes obtained from T2D patients were injected into cutaneous mouse wounds or applied to HUVECs. Mechanistically, the miR-20b-mediated suppression of WNT9 led to impaired angiogenesis, while the silencing of miR-20b promoted wound healing in vivo [ 231 ]. Circulating exosomes, enriched with miR-15a and extracted from serum of diabetic patients, inhibited wound healing both in vitro an in vivo through the inhibition of the NOX5/ROS signaling pathway, while the inhibition of miR-15a improved wound closure, blood perfusion and angiogenesis [ 232 ].…”

Extracellular vesicle‐carried microRNA‐27b derived from mesenchymal stem cells accelerates cutaneous wound healing via E3 ubiquitin ligase ITCH

“…Moreover, EVs derived from human umbilical cord‐blood MSCs have been reported to accelerate human skin regeneration 11 . Importantly, EV‐carried microRNAs (miRNAs or miRs) have been revealed to display potentially therapeutic roles in diabetes‐related impaired wound healing 12 . It has been highlighted that the transformation of anti‐inflammatory RNAs from stem cells to injury sites mediated by EVs could coordinate the inflammatory responses and immune alleviation, thereby better facilitating the healing processes, which exerts a value and potential for the therapeutic approaches in regenerative medicine 13 …”