Exosomes from Circ-Astn1-modified Adipose-derived Mesenchymal Stem Cells Enhance Wound Healing Through MiR-138-5p/SIRT1/FOXO1 Axis Regulation

Overview

Journal World J Stem Cells

Publisher Baishideng Publishing Group

Date 2023 Jun 21

PMID 37342222

Authors

Zhi Wang

Cheng Feng

Hao Liu

Tian Meng

Wei-Qing Huang

Ke-Xin Song

You-Bin Wang

Affiliations

Soon will be listed here.

Abstract

Background: Wound healing impairment is a dysfunction induced by hyperglycemia and its effect on endothelial precursor cells (EPCs) in type 2 diabetes mellitus. There is increasing evidence showing that exosomes (Exos) derived from adipose-derived mesenchymal stem cells (ADSCs) exhibit the potential to improve endothelial cell function along with wound healing. However, the potential therapeutic mechanism by which ADSC Exos contribute to wound healing in diabetic mice remains unclear.

Aim: To reveal the potential therapeutic mechanism of ADSC Exos in wound healing in diabetic mice.

Methods: Exos from ADSCs and fibroblasts were used for high-throughput RNA sequencing (RNA-Seq). ADSC-Exo-mediated healing of full-thickness skin wounds in a diabetic mouse model was investigated. We employed EPCs to investigate the therapeutic function of Exos in cell damage and dysfunction caused by high glucose (HG). We utilized a luciferase reporter (LR) assay to analyze interactions among circular RNA astrotactin 1 (circ-Astn1), sirtuin (SIRT) and miR-138-5p. A diabetic mouse model was used to verify the therapeutic effect of circ-Astn1 on Exo-mediated wound healing.

Results: High-throughput RNA-Seq analysis showed that circ-Astn1 expression was increased in ADSC Exos compared with Exos from fibroblasts. Exos containing high concentrations of circ-Astn1 had enhanced therapeutic effects in restoring EPC function under HG conditions by promoting SIRT1 expression. Circ-Astn1 expression enhanced SIRT1 expression through miR-138-5p adsorption, which was validated by the LR assay along with bioinformatics analyses. Exos containing high concentrations of circ-Astn1 had better therapeutic effects on wound healing compared to wild-type ADSC Exos. Immunofluorescence and immunohistochemical investigations suggested that circ-Astn1 enhanced angiopoiesis through Exo treatment of wounded skin as well as by suppressing apoptosis through promotion of SIRT1 and decreased forkhead box O1 expression.

Conclusion: Circ-Astn1 promotes the therapeutic effect of ADSC-Exos and thus improves wound healing in diabetes miR-138-5p absorption and SIRT1 upregulation. Based on our data, we advocate targeting the circ-Astn1/miR-138-5p/SIRT1 axis as a potential therapeutic option for the treatment of diabetic ulcers.

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References

Zhu K, Hu X, Chen H, Li F, Yin N, Liu A . Downregulation of circRNA DMNT3B contributes to diabetic retinal vascular dysfunction through targeting miR-20b-5p and BAMBI. EBioMedicine. 2019; 49:341-353. PMC: 6945224. DOI: 10.1016/j.ebiom.2019.10.004. View

Li R, Chen C, Zheng R, Zou L, Hao G, Zhang G . Influences of hucMSC-exosomes on VEGF and BMP-2 expression in SNFH rats. Eur Rev Med Pharmacol Sci. 2019; 23(7):2935-2943. DOI: 10.26355/eurrev_201904_17573. View

Leszczynska A, Kulkarni M, Ljubimov A, Saghizadeh M . Exosomes from normal and diabetic human corneolimbal keratocytes differentially regulate migration, proliferation and marker expression of limbal epithelial cells. Sci Rep. 2018; 8(1):15173. PMC: 6182003. DOI: 10.1038/s41598-018-33169-5. View

Wang A, Toma M, Ma J, Li D, Vij M, Chu T . Circular RNA hsa_circ_0084443 Is Upregulated in Diabetic Foot Ulcer and Modulates Keratinocyte Migration and Proliferation. Adv Wound Care (New Rochelle). 2020; 9(4):145-160. PMC: 7047102. DOI: 10.1089/wound.2019.0956. View

Qian C, Liang S, Wan G, Dong Y, Lu T, Yan P . Salidroside alleviates high-glucose-induced injury in retinal pigment epithelial cell line ARPE-19 by down-regulation of miR-138. RNA Biol. 2019; 16(10):1461-1470. PMC: 6779393. DOI: 10.1080/15476286.2019.1637696. View

Shi R, Jin Y, Hu W, Lian W, Cao C, Han S . Exosomes derived from mmu_circ_0000250-modified adipose-derived mesenchymal stem cells promote wound healing in diabetic mice by inducing miR-128-3p/SIRT1-mediated autophagy. Am J Physiol Cell Physiol. 2020; 318(5):C848-C856. DOI: 10.1152/ajpcell.00041.2020. View

He M, Wang W, Yu H, Wang D, Cao D, Zeng Y . Comparison of expression profiling of circular RNAs in vitreous humour between diabetic retinopathy and non-diabetes mellitus patients. Acta Diabetol. 2019; 57(4):479-489. DOI: 10.1007/s00592-019-01448-w. View

Hu J, Wang W, Lan X, Zeng Z, Liang Y, Yan Y . CAFs secreted exosomes promote metastasis and chemotherapy resistance by enhancing cell stemness and epithelial-mesenchymal transition in colorectal cancer. Mol Cancer. 2019; 18(1):91. PMC: 6503554. DOI: 10.1186/s12943-019-1019-x. View

Okonkwo U, Chen L, Ma D, Haywood V, Barakat M, Urao N . Compromised angiogenesis and vascular Integrity in impaired diabetic wound healing. PLoS One. 2020; 15(4):e0231962. PMC: 7179900. DOI: 10.1371/journal.pone.0231962. View

10.

Yan X, Yu A, Zheng H, Wang S, He Y, Wang L . Calycosin-7----glucoside Attenuates OGD/R-Induced Damage by Preventing Oxidative Stress and Neuronal Apoptosis via the SIRT1/FOXO1/PGC-1 Pathway in HT22 Cells. Neural Plast. 2019; 2019:8798069. PMC: 6915014. DOI: 10.1155/2019/8798069. View

11.

Potente M, Ghaeni L, Baldessari D, Mostoslavsky R, Rossig L, Dequiedt F . SIRT1 controls endothelial angiogenic functions during vascular growth. Genes Dev. 2007; 21(20):2644-58. PMC: 2000327. DOI: 10.1101/gad.435107. View

12.

Ren B, Zhang Y, Liu S, Cheng X, Yang X, Cui X . Curcumin alleviates oxidative stress and inhibits apoptosis in diabetic cardiomyopathy via Sirt1-Foxo1 and PI3K-Akt signalling pathways. J Cell Mol Med. 2020; 24(21):12355-12367. PMC: 7687015. DOI: 10.1111/jcmm.15725. View

13.

An R, Zhang Y, Qiao Y, Song L, Wang H, Dong X . Adipose stem cells isolated from diabetic mice improve cutaneous wound healing in streptozotocin-induced diabetic mice. Stem Cell Res Ther. 2020; 11(1):120. PMC: 7079496. DOI: 10.1186/s13287-020-01621-x. View

14.

Qiu J, Shu C, Li X, Ye C, Zhang W . Exosomes from linc00511-overexpressing ADSCs accelerates angiogenesis in diabetic foot ulcers healing by suppressing PAQR3-induced Twist1 degradation. Diabetes Res Clin Pract. 2021; 180:109032. DOI: 10.1016/j.diabres.2021.109032. View

15.

Xia L, Song M . Role of Non-coding RNA in Diabetic Cardiomyopathy. Adv Exp Med Biol. 2020; 1229:181-195. DOI: 10.1007/978-981-15-1671-9_10. View

16.

Li G, Peng H, Qian S, Zou X, Du Y, Wang Z . Bone Marrow-Derived Mesenchymal Stem Cells Restored High-Fat-Fed Induced Hyperinsulinemia in Rats at Early Stage of Type 2 Diabetes Mellitus. Cell Transplant. 2020; 29:963689720904628. PMC: 7502689. DOI: 10.1177/0963689720904628. View

17.

Al-Shamsi M, Amin A, Adeghate E . Vitamin E ameliorates some biochemical parameters in normal and diabetic rats. Ann N Y Acad Sci. 2006; 1084:411-31. DOI: 10.1196/annals.1372.033. View

18.

Guo S, Tao S, Yin W, Qi X, Yuan T, Zhang C . Exosomes derived from platelet-rich plasma promote the re-epithelization of chronic cutaneous wounds via activation of YAP in a diabetic rat model. Theranostics. 2017; 7(1):81-96. PMC: 5196887. DOI: 10.7150/thno.16803. View

19.

Huang X, Sun J, Chen G, Niu C, Wang Y, Zhao C . Resveratrol Promotes Diabetic Wound Healing via SIRT1-FOXO1-c-Myc Signaling Pathway-Mediated Angiogenesis. Front Pharmacol. 2019; 10:421. PMC: 6491521. DOI: 10.3389/fphar.2019.00421. View

20.

Al-Shamsi M, Amin A, Adeghate E . Effect of vitamin C on liver and kidney functions in normal and diabetic rats. Ann N Y Acad Sci. 2006; 1084:371-90. DOI: 10.1196/annals.1372.031. View