Signal transduction mechanism of exosomes in diabetic complications (Review)

Li,Xueting; Shi,Shuo; Jing,Dehuai; Li,Xinjian; Zhang,Bin; Bie,Qingli

doi:10.3892/etm.2021.11078

Signal transduction mechanism of exosomes in diabetic complications (Review)

Authors:
- Xueting Li
- Shuo Shi
- Dehuai Jing
- Xinjian Li
- Bin Zhang
- Qingli Bie
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Affiliations: Department of Clinical Medicine, Jining Medical University, Jining, Shandong 272000, P.R. China, Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, P.R. China, Department of Digestive Endoscopy, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, P.R. China, Department of Nephrology, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, P.R. China
Published online on: December 17, 2021 https://doi.org/10.3892/etm.2021.11078
Article Number: 155

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Abstract

Exosomes are vesicles with a particle size of 30‑120 nm that are secreted by cells through exocytosis. The composition of an exosome includes a lipid bilayer and its internal package of biological molecules, such as proteins, ribonucleotides and deoxyribonucleotides. Diabetes is a chronic and refractory disease. The complications induced by high blood glucose have become a major problem in global public health and the pathogenesis of diabetic complications remains to be fully elucidated. In recent years, it has been gradually recognized that exosomes from different cell sources and their related molecules, particularly exosomal proteins and microRNAs, have an important role in the pathogenesis of diabetic complications, allowing for the exploration of the pathogenesis of diabetic complications from a molecular perspective. The present review summarizes the latest studies on exosomes from different cell sources in the pathogenesis of diabetic complications, which may provide novel targets for the prevention and treatment of diabetic complications.

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1	Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, Colagiuri S, Guariguata L, Motala AA, Ogurtsova K, et al: Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the international diabetes federation diabetes atlas, 9th edition. Diabetes Res Clin Pract. 157(107843)2019.PubMed/NCBI View Article : Google Scholar
2	Thomas CC and Philipson LH: Update on diabetes classification. Med Clin North Am. 99:1–16. 2015.PubMed/NCBI View Article : Google Scholar
3	Müller G: Microvesicles/exosomes as potential novel biomarkers of metabolic diseases. Diabetes Metab Syndr Obes. 5:247–282. 2012.PubMed/NCBI View Article : Google Scholar
4	Ying W, Riopel M, Bandyopadhyay G, Dong Y, Birmingham A, Seo JB, Ofrecio JM, Wollam J, Hernandez-Carretero A, Fu W, et al: Adipose tissue macrophage-derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity. Cell. 171:372–384.e12. 2017.PubMed/NCBI View Article : Google Scholar
5	Lin J, Li J, Huang B, Liu J, Chen X, Chen XM, Xu YM, Huang LF and Wang XZ: Exosomes: Novel biomarkers for clinical diagnosis. ScientificWorldJournal. 2015(657086)2015.PubMed/NCBI View Article : Google Scholar
6	Kalluri R and LeBleu VS: The biology, function, and biomedical applications of exosomes. Science. 367(eaau6977)2020.PubMed/NCBI View Article : Google Scholar
7	Théry C, Zitvogel L and Amigorena S: Exosomes: Composition, biogenesis and function. Nat Rev Immunol. 2:569–579. 2002.PubMed/NCBI View Article : Google Scholar
8	Doyle LM and Wang MZ: Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome isolation and analysis. Cells. 8(727)2019.PubMed/NCBI View Article : Google Scholar
9	Pegtel DM and Gould SJ: Exosomes. Annu Rev Biochem. 88:487–514. 2019.PubMed/NCBI View Article : Google Scholar
10	Zhang J, Li S, Li L, Li M, Guo C, Yao J and Mi S: Exosome and exosomal microRNA: Trafficking, sorting, and function. Genomics Proteomics Bioinformatics. 13:17–24. 2015.PubMed/NCBI View Article : Google Scholar
11	Lebovitz HE: Etiology and pathogenesis of diabetes mellitus. Pediatr Clin North Am. 31:521–530. 1984.PubMed/NCBI View Article : Google Scholar
12	Kaul K, Tarr JM, Ahmad SI, Kohner EM and Chibber R: Introduction to diabetes mellitus. Adv Exp Med Biol. 771:1–11. 2012.PubMed/NCBI View Article : Google Scholar
13	Forbes JM and Cooper ME: Mechanisms of diabetic complications. Physiol Rev. 93:137–188. 2013.PubMed/NCBI View Article : Google Scholar
14	Jin J, Shi Y, Gong J, Zhao L, Li Y, He Q and Huang H: Exosome secreted from adipose-derived stem cells attenuates diabetic nephropathy by promoting autophagy flux and inhibiting apoptosis in podocyte. Stem Cell Res Ther. 10(95)2019.PubMed/NCBI View Article : Google Scholar
15	Chang W and Wang J: Exosomes and their noncoding RNA cargo are emerging as new modulators for diabetes mellitus. Cells. 8(853)2019.PubMed/NCBI View Article : Google Scholar
16	Castaño C, Novials A and Párrizas M: Exosomes and diabetes. Diabetes Metab Res Rev. 35(e3107)2019.PubMed/NCBI View Article : Google Scholar
17	Kakleas K, Soldatou A, Karachaliou F and Karavanaki K: Associated autoimmune diseases in children and adolescents with type 1 diabetes mellitus (T1DM). Autoimmun Rev. 14:781–797. 2015.PubMed/NCBI View Article : Google Scholar
18	Cianciaruso C, Phelps EA, Pasquier M, Hamelin R, Demurtas D, Alibashe Ahmed M, Piemonti L, Hirosue S, Swartz MA, De Palma M, et al: Primary human and rat β-cells release the intracellular autoantigens GAD65, IA-2, and proinsulin in exosomes together with cytokine-induced enhancers of immunity. Diabetes. 66:460–473. 2017.PubMed/NCBI View Article : Google Scholar
19	Rahman MJ, Regn D, Bashratyan R and Dai YD: Exosomes released by islet-derived mesenchymal stem cells trigger autoimmune responses in NOD mice. Diabetes. 63:1008–1020. 2014.PubMed/NCBI View Article : Google Scholar
20	Garcia-Contreras M, Brooks RW, Boccuzzi L, Robbins PD and Ricordi C: Exosomes as biomarkers and therapeutic tools for type 1 diabetes mellitus. Eur Rev Med Pharmacol Sci. 21:2940–2956. 2017.PubMed/NCBI
21	Tsukita S, Yamada T, Takahashi K, Munakata Y, Hosaka S, Takahashi H, Gao J, Shirai Y, Kodama S, Asai Y, et al: MicroRNAs 106b and 222 improve hyperglycemia in a mouse model of insulin-deficient diabetes via pancreatic β-cell proliferation. EBioMedicine. 15:163–172. 2017.PubMed/NCBI View Article : Google Scholar
22	Malone JI and Hansen BC: Does obesity cause type 2 diabetes mellitus (T2DM)? Or is it the opposite? Pediatr Diabetes. 20:5–9. 2019.PubMed/NCBI View Article : Google Scholar
23	Heydemann A: An overview of murine high fat diet as a model for type 2 diabetes mellitus. J Diabetes Res. 2016(2902351)2016.PubMed/NCBI View Article : Google Scholar
24	Zhao H, Shang Q, Pan Z, Bai Y, Li Z, Zhang H, Zhang Q, Guo C, Zhang L and Wang Q: Exosomes from adipose-derived stem cells attenuate adipose inflammation and obesity through polarizing m2 macrophages and beiging in white adipose tissue. Diabetes. 67:235–247. 2018.PubMed/NCBI View Article : Google Scholar
25	Castaño C, Kalko S, Novials A and Párrizas M: Obesity-associated exosomal miRNAs modulate glucose and lipid metabolism in mice. Proc Natl Acad Sci USA. 115:12158–12163. 2018.PubMed/NCBI View Article : Google Scholar
26	Brown AE and Walker M: Genetics of insulin resistance and the metabolic syndrome. Curr Cardiol Rep. 18(75)2016.PubMed/NCBI View Article : Google Scholar
27	Sun Y, Shi H, Yin S, Ji C, Zhang X, Zhang B, Wu P, Shi Y, Mao F, Yan Y, et al: Human mesenchymal stem cell derived exosomes alleviate type 2 diabetes mellitus by reversing peripheral insulin resistance and relieving β-cell destruction. ACS Nano. 12:7613–7628. 2018.PubMed/NCBI View Article : Google Scholar
28	Cole JB and Florez JC: Genetics of diabetes mellitus and diabetes complications. Nat Rev Nephrol. 16:377–390. 2020.PubMed/NCBI View Article : Google Scholar
29	Barrett EJ, Liu Z, Khamaisi M, King GL, Klein R, Klein BEK, Hughes TM, Craft S, Freedman BI, Bowden DW, et al: Diabetic microvascular disease: An endocrine society scientific statement. J Clin Endocrinol Metab. 102:4343–4410. 2017.PubMed/NCBI View Article : Google Scholar
30	Shen B, Liu J, Zhang F, Wang Y, Qin Y, Zhou Z, Qiu J and Fan Y: CCR2 positive exosome released by mesenchymal stem cells suppresses macrophage functions and alleviates ischemia/reperfusion-induced renal injury. Stem Cells Int. 2016(1240301)2016.PubMed/NCBI View Article : Google Scholar
31	Liang X, Zhang L, Wang S, Han Q and Zhao RC: Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a. J Cell Sci. 129:2182–2189. 2016.PubMed/NCBI View Article : Google Scholar
32	Chimenti MS, Ballanti E, Triggianese P and Perricone R: Vasculitides and the complement system: A comprehensive review. Clin Rev Allergy Immunol. 49:333–346. 2015.PubMed/NCBI View Article : Google Scholar
33	Huang C, Fisher KP, Hammer SS, Navitskaya S, Blanchard GJ and Busik JV: Plasma exosomes contribute to microvascular damage in diabetic retinopathy by activating the classical complement pathway. Diabetes. 67:1639–1649. 2018.PubMed/NCBI View Article : Google Scholar
34	Martínez-Castelao A, Navarro-González JF, Górriz JL and de Alvaro F: The concept and the epidemiology of diabetic nephropathy have changed in recent years. J Clin Med. 4:1207–1216. 2015.PubMed/NCBI View Article : Google Scholar
35	Zhang L, Li R, Shi W, Liang X, Liu S, Ye Z, Yu C, Chen Y, Zhang B, Wang W, et al: NFAT2 inhibitor ameliorates diabetic nephropathy and podocyte injury in db/db mice. Br J Pharmacol. 170:426–439. 2013.PubMed/NCBI View Article : Google Scholar
36	Ioannou K: Diabetic nephropathy: Is it always there? Assumptions, weaknesses and pitfalls in the diagnosis. Hormones (Athens). 16:351–361. 2017.PubMed/NCBI View Article : Google Scholar
37	Sakurai A, Ono H, Ochi A, Matsuura M, Yoshimoto S, Kishi S, Murakami T, Tominaga T, Nagai K, Abe H and Doi T: Involvement of Elf3 on Smad3 activation-dependent injuries in podocytes and excretion of urinary exosome in diabetic nephropathy. PLoS One. 14(e0216788)2019.PubMed/NCBI View Article : Google Scholar
38	Abe H, Sakurai A, Ono H, Hayashi S, Yoshimoto S, Ochi A, Ueda S, Nishimura K, Shibata E, Tamaki M, et al: Urinary exosomal mRNA of WT1 as diagnostic and prognostic biomarker for diabetic nephropathy. J Med Invest. 65:208–215. 2018.PubMed/NCBI View Article : Google Scholar
39	Kim H, Bae YU, Jeon JS, Noh H, Park HK, Byun DW, Han DC, Ryu S and Kwon SH: The circulating exosomal microRNAs related to albuminuria in patients with diabetic nephropathy. J Transl Med. 17(236)2019.PubMed/NCBI View Article : Google Scholar
40	Calle P and Hotter G: Macrophage phenotype and fibrosis in diabetic nephropathy. Int J Mol Sci. 21(2806)2020.PubMed/NCBI View Article : Google Scholar
41	Wang T, Zhu H, Yang S and Fei X: Let-7a-5p may participate in the pathogenesis of diabetic nephropathy through targeting HMGA2. Mol Med Rep. 19:4229–4237. 2019.PubMed/NCBI View Article : Google Scholar
42	Ding Y and Choi ME: Regulation of autophagy by TGF-β: Emerging role in kidney fibrosis. Semin Nephrol. 34:62–71. 2014.PubMed/NCBI View Article : Google Scholar
43	Tervaert TW, Mooyaart AL, Amann K, Cohen AH, Cook HT, Drachenberg CB, Ferrario F, Fogo AB, Haas M, de Heer E, et al: Pathologic classification of diabetic nephropathy. J Am Soc Nephrol. 21:556–563. 2010.PubMed/NCBI View Article : Google Scholar
44	Jia Y, Zheng Z, Xue M, Zhang S, Hu F, Li Y, Yang Y, Zou M, Li S, Wang L, et al: Extracellular vesicles from albumin-induced tubular epithelial cells promote the M1 macrophage phenotype by targeting klotho. Mol Ther. 27:1452–1466. 2019.PubMed/NCBI View Article : Google Scholar
45	Ding Y and Choi ME: Autophagy in diabetic nephropathy. J Endocrinol. 224:R15–R30. 2015.PubMed/NCBI View Article : Google Scholar
46	Lu Q, Wang WW, Zhang MZ, Ma ZX, Qiu XR, Shen M and Yin XX: ROS induces epithelial-mesenchymal transition via the TGF-β1/PI3K/Akt/mTOR pathway in diabetic nephropathy. Exp Ther Med. 17:835–846. 2019.PubMed/NCBI View Article : Google Scholar
47	Antonetti DA, Klein R and Gardner TW: Diabetic retinopathy. N Engl J Med. 366:1227–1239. 2012.PubMed/NCBI View Article : Google Scholar
48	Mazzeo A, Beltramo E, Lopatina T, Gai C, Trento M and Porta M: Molecular and functional characterization of circulating extracellular vesicles from diabetic patients with and without retinopathy and healthy subjects. Exp Eye Res. 176:69–77. 2018.PubMed/NCBI View Article : Google Scholar
49	Heng LZ, Comyn O, Peto T, Tadros C, Ng E, Sivaprasad S and Hykin PG: Diabetic retinopathy: Pathogenesis, clinical grading, management and future developments. Diabet Med. 30:640–650. 2013.PubMed/NCBI View Article : Google Scholar
50	Shosha E, Xu Z, Narayanan SP, Lemtalsi T, Fouda AY, Rojas M, Xing J, Fulton D, Caldwell RW and Caldwell RB: Mechanisms of diabetes-induced endothelial cell senescence: Role of arginase 1. Int J Mol Sci. 19(1215)2018.PubMed/NCBI View Article : Google Scholar
51	Naruse R, Suetsugu M, Terasawa T, Ito K, Hara K, Takebayashi K, Morita K, Aso Y and Inukai T: Oxidative stress and antioxidative potency are closely associated with diabetic retinopathy and nephropathy in patients with type 2 diabetes. Saudi Med J. 34:135–141. 2013.PubMed/NCBI
52	Zhang W, Dong X, Wang T and Kong Y: Exosomes derived from platelet-rich plasma mediate hyperglycemia-induced retinal endothelial injury via targeting the TLR4 signaling pathway. Exp Eye Res. 189(107813)2019.PubMed/NCBI View Article : Google Scholar
53	Shao L, Zhang Y, Lan B, Wang J, Zhang Z, Zhang L, Xiao P, Meng Q, Geng YJ, Yu XY and Li Y: MiRNA-sequence indicates that mesenchymal stem cells and exosomes have similar mechanism to enhance cardiac repair. Biomed Res Int. 2017(4150705)2017.PubMed/NCBI View Article : Google Scholar
54	Vujosevic S, Micera A, Bini S, Berton M, Esposito G and Midena E: Proteome analysis of retinal glia cells-related inflammatory cytokines in the aqueous humour of diabetic patients. Acta Ophthalmol. 94:56–64. 2016.PubMed/NCBI View Article : Google Scholar
55	Liu C, Ge HM, Liu BH, Dong R, Shan K, Chen X, Yao MD, Li XM, Yao J, Zhou RM, et al: Targeting pericyte-endothelial cell crosstalk by circular RNA-cPWWP2A inhibition aggravates diabetes-induced microvascular dysfunction. Proc Natl Acad Sci USA. 116:7455–7464. 2019.PubMed/NCBI View Article : Google Scholar
56	Dillmann WH: Diabetic cardiomyopathy. Circ Res. 124:1160–1162. 2019.PubMed/NCBI View Article : Google Scholar
57	Bugger H and Abel ED: Molecular mechanisms of diabetic cardiomyopathy. Diabetologia. 57:660–671. 2014.PubMed/NCBI View Article : Google Scholar
58	Jia G, Demarco VG and Sowers JR: Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy. Nat Rev Endocrinol. 12:144–153. 2016.PubMed/NCBI View Article : Google Scholar
59	Liu X, Song X, Lu J, Chen X, Liang E, Liu X, Zhang M, Zhang Y, Du Z and Zhao Y: Neferine inhibits proliferation and collagen synthesis induced by high glucose in cardiac fibroblasts and reduces cardiac fibrosis in diabetic mice. Oncotarget. 7:61703–61715. 2016.PubMed/NCBI View Article : Google Scholar
60	Schenk S, McCurdy CE, Philp A, Chen MZ, Holliday MJ, Bandyopadhyay GK, Osborn O, Baar K and Olefsky JM: Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction. J Clin Invest. 121:4281–4288. 2011.PubMed/NCBI View Article : Google Scholar
61	Tao S, Chen L, Song J, Zhu N, Song X, Shi R, Ge G and Zhang Y: Tanshinone IIA ameliorates diabetic cardiomyopathy by inhibiting Grp78 and CHOP expression in STZ-induced diabetes rats. Exp Ther Med. 18:729–734. 2019.PubMed/NCBI View Article : Google Scholar
62	Wang X, Huang W, Liu G, Cai W, Millard RW, Wang Y, Chang J, Peng T and Fan GC: Cardiomyocytes mediate anti-angiogenesis in type 2 diabetic rats through the exosomal transfer of miR-320 into endothelial cells. J Mol Cell Cardiol. 74:139–150. 2014.PubMed/NCBI View Article : Google Scholar
63	Hu J, Wang S, Xiong Z, Cheng Z, Yang Z, Lin J, Wang T, Feng X, Gao E, Wang H and Sun D: Exosomal Mst1 transfer from cardiac microvascular endothelial cells to cardiomyocytes deteriorates diabetic cardiomyopathy. Biochim Biophys Acta Mol Basis Dis. 1864:3639–3649. 2018.PubMed/NCBI View Article : Google Scholar
64	Quinaglia T, Oliveira DC, Matos-Souza JR and Sposito AC: Diabetic cardiomyopathy: Factual or factoid? Rev Assoc Med Bras (1992). 65:61–69. 2019.PubMed/NCBI View Article : Google Scholar
65	Feldman EL, Callaghan BC, Pop-Busui R, Zochodne DW, Wright DE, Bennett DL, Bril V, Russell JW and Viswanathan V: Diabetic neuropathy. Nat Rev Dis Primers. 5(41)2019.PubMed/NCBI View Article : Google Scholar
66	Ma J, Yu H, Liu J, Chen Y, Wang Q and Xiang L: Metformin attenuates hyperalgesia and allodynia in rats with painful diabetic neuropathy induced by streptozotocin. Eur J Pharmacol. 764:599–606. 2015.PubMed/NCBI View Article : Google Scholar
67	Yin Z, Han Z, Hu T, Zhang S, Ge X, Huang S, Wang L, Yu J, Li W, Wang Y, et al: Neuron-derived exosomes with high miR-21-5p expression promoted polarization of M1 microglia in culture. Brain Behav Immun. 83:270–282. 2020.PubMed/NCBI View Article : Google Scholar
68	Feng Y, Chen L, Luo Q, Wu M, Chen Y and Shi X: Involvement of microRNA-146a in diabetic peripheral neuropathy through the regulation of inflammation. Drug Des Devel Ther. 12:171–177. 2018.PubMed/NCBI View Article : Google Scholar
69	Jia L, Chopp M, Wang L, Lu X, Szalad A and Zhang ZG: Exosomes derived from high-glucose-stimulated Schwann cells promote development of diabetic peripheral neuropathy. FASEB J. 32(fj201800597R)2018.PubMed/NCBI View Article : Google Scholar
70	Alomar SY, Gheit R, Enan ET, El-Bayoumi KS, Shoaeir MZ, Elkazaz AY, Al Thagfan SS, Zaitone SA and El-Sayed RM: Novel mechanism for memantine in attenuating diabetic neuropathic pain in mice via downregulating the spinal HMGB1/TRL4/NF-kB inflammatory axis. Pharmaceuticals (Basel). 14(307)2021.PubMed/NCBI View Article : Google Scholar
71	Chen Q, Zhang D, Wang L, Zhang Y, Chen H, Chen F and He Z: Effect of intermittent high glucose on oxygen-glucose deprivation/refurnish neuronal survival. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 31:61–66. 2019.PubMed/NCBI View Article : Google Scholar : (In Chinese).
72	Bonomelli B, Martegani E and Colombo S: Lack of SNF1 induces localization of active Ras in mitochondria and triggers apoptosis in the yeast saccharomyces cerevisiae. Biochem Biophys Res Commun. 523:130–134. 2020.PubMed/NCBI View Article : Google Scholar
73	Boulton AJ: Diabetic neuropathy and foot complications. Handb Clin Neurol. 126:97–107. 2014.PubMed/NCBI View Article : Google Scholar
74	Noor S, Zubair M and Ahmad J: Diabetic foot ulcer-a review on pathophysiology, classification and microbial etiology. Diabetes Metab Syndr. 9:192–199. 2015.PubMed/NCBI View Article : Google Scholar
75	Li X, Xie X, Lian W, Shi R, Han S, Zhang H, Lu L and Li M: Exosomes from adipose-derived stem cells overexpressing Nrf2 accelerate cutaneous wound healing by promoting vascularization in a diabetic foot ulcer rat model. Exp Mol Med. 50:1–14. 2018.PubMed/NCBI View Article : Google Scholar
76	Zhu B, Zhang L, Liang C, Liu B, Pan X, Wang Y, Zhang Y, Zhang Y, Xie W, Yan B, et al: Stem cell-derived exosomes prevent aging-induced cardiac dysfunction through a novel exosome/lncRNA MALAT1/NF-κB/TNF-α signaling pathway. Oxid Med Cell Longev. 2019(9739258)2019.PubMed/NCBI View Article : Google Scholar
77	Harrell CR, Jovicic N, Djonov V, Arsenijevic N and Volarevic V: Mesenchymal stem cell-derived exosomes and other extracellular vesicles as new remedies in the therapy of inflammatory diseases. Cells. 8(1605)2019.PubMed/NCBI View Article : Google Scholar
78	Li M, Wang T, Tian H, Wei G, Zhao L and Shi Y: Macrophage-derived exosomes accelerate wound healing through their anti-inflammation effects in a diabetic rat model. Artif Cells Nanomed Biotechnol. 47:3793–3803. 2019.PubMed/NCBI View Article : Google Scholar
79	Chen O, Donnelly CR and Ji RR: Regulation of pain by neuro-immune interactions between macrophages and nociceptor sensory neurons. Curr Opin Neurobiol. 62:17–25. 2020.PubMed/NCBI View Article : Google Scholar :  Qing L, Chen H, Tang J and Jia X: Exosomes and their MicroRNA cargo: New players in peripheral nerve regeneration. Neurorehabil Neural Repair 32, 765-776, 2018.
80	Qing L, Chen H, Tang J and Jia X: Exosomes and Their MicroRNA Cargo: New Players in Peripheral Nerve Regeneration. Neurorehabil Neural Repair. 32:765–776. 2018.PubMed/NCBI View Article : Google Scholar
81	Dalirfardouei R, Jamialahmadi K, Jafarian AH and Mahdipour E: Promising effects of exosomes isolated from menstrual blood-derived mesenchymal stem cell on wound-healing process in diabetic mouse model. J Tissue Eng Regen Med. 13:555–568. 2019.PubMed/NCBI View Article : Google Scholar
82	DeFronzo RA, Ferrannini E, Groop L, Henry RR, Herman WH, Holst JJ, Hu FB, Kahn CR, Raz I, Shulman GI, et al: Type 2 diabetes mellitus. Nat Rev Dis Primers. 1(15019)2015.PubMed/NCBI View Article : Google Scholar
83	Cho JA, Yeo DJ, Son HY, Kim HW, Jung DS, Ko JK, Koh JS, Kim YN and Kim CW: Exosomes: A new delivery system for tumor antigens in cancer immunotherapy. Int J Cancer. 114:613–622. 2005.PubMed/NCBI View Article : Google Scholar
84	Rani S, Ryan AE, Griffin MD and Ritter T: Mesenchymal stem cell-derived extracellular vesicles: Toward cell-free therapeutic applications. Mol Ther. 23:812–823. 2015.PubMed/NCBI View Article : Google Scholar
85	Zhang Y, Bi J, Huang J, Tang Y, Du S and Li P: Exosome: A review of its classification, isolation techniques, storage, diagnostic and targeted therapy applications. Int J Nanomedicine. 15:6917–6934. 2020.PubMed/NCBI View Article : Google Scholar