Endothelial progenitor cell derived exosomes mediated miR-182-5p delivery accelerate diabetic wound healing via down-regulating PPARG

Abstract

Diabetic wound is one of the most common and serious complications of diabetes, which is characterized by abnormal number and quality of wound repair related cells. Previous studies have shown that human endothelial progenitor cells derived exosomes (EPCs-EXO) can promote diabetic wound healing through modulating vascular endothelial cell function. The purpose of this study was to investigate the biological effects and molecular mechanisms of EPCs-EXO on diabetic wound healing. The regulation of EPCs-EXO on human immortalized epidermal cell line HaCaT in high glucose (HG) environment was evaluated. Our data showed that EPCs-EXO promoted the proliferation, migration, while inhibited apoptosis of HaCaTs challenged by HG via elevating miR-182-5p expression level in vitro. Skin wound healing was significantly enhanced by EPCs-EXO in diabetic mice. Moreover, bioinformatics analyses and luciferase reporter assay indicated that exosomal miR-182-5p was bound to PPARG 3' UTR sequence and inhibited the expression of PPARG. Collectively, our findings provided a new role of EPCs-EXO in the clinical treatment of diabetic skin wounds. Diabetic wound is one of the most common and serious complications of diabetes, which is characterized by abnormal number and quality of wound repair related cells. Previous studies have shown that human endothelial progenitor cells derived exosomes (EPCs-EXO) can promote diabetic wound healing through modulating vascular endothelial cell function. The purpose of this study was to investigate the biological effects and molecular mechanisms of EPCs-EXO on diabetic wound healing. The regulation of EPCs-EXO on human immortalized epidermal cell line HaCaT in high glucose (HG) environment was evaluated. Our data showed that EPCs-EXO promoted the proliferation, migration, while inhibited apoptosis of HaCaTs challenged by HG via elevating miR-182-5p expression level in vitro. Skin wound healing was significantly enhanced by EPCs-EXO in diabetic mice. Moreover, bioinformatics analyses and luciferase reporter assay indicated that exosomal miR-182-5p was bound to PPARG 3' UTR sequence and inhibited the expression of PPARG. Collectively, our findings provided a new role of EPCs-EXO in the clinical treatment of diabetic skin wounds.

Therapeutic Applications of Stem Cell-Derived Exosomes

“…Similarly, MSC-exos can promote the migration and proliferation of vital cell types such as keratinocytes and fibroblasts during the proliferative stage [ 167 ]. This promotion is achieved through the inhibition of specific signaling pathways, including Large tumor suppressor kinase 2 (LATS2) [ 168 ], Peroxisome proliferator-activated receptor γ (PPARγ) [ 169 ], and Apoptosis-inducing factor (AIF) nucleus translocation [ 170 ], while concurrently activating others, such as PI3K/Akt [ 171 ], Akt/Hypoxia-Inducible Factor 1 alpha (HIF-1α) [ 171 , 172 ], ERK1/2 [ 173 ], and Wnt/β-catenin [ 174 ].…”

Stem Cell-Derived Extracellular Vesicles: Promising Therapeutic Opportunities for Diabetic Wound Healing

“… 98 Li et al verified that upregulated miR-182-5p containing EPC-exos improved the ability of proliferation, and migration, and inhibited apoptosis in HaCaT cells, accelerating the process of wound healing in diabetic mice by inhibiting PPARG expression. 99 Furthermore, preprocessing can enhance the beneficial impact of EVs. For instance, astragaloside IV pretreatment could efficiently boost the secretion of EVs.…”

Exosomes: The emerging mechanisms and potential clinical applications in dermatology

“…ESC-exos regulated the phosphatidylinositol-3 kinase/protein kinase B and TGF-β signaling pathways via delivering miRNAs 81 . Endothelial progenitor cell-derived exosomes (EPC-exos) promoted proliferation and migration while inhibiting apoptosis of HaCaTs challenged by HG via miR-182-5p/ PPARG axis, thus accelerating diabetic wound healing 82 . EPC-exos promoted angiogenesis in diabetic wound healing via delivering miRNA-221-3p 83 .…”