Generic placeholder image

Current Stem Cell Research & Therapy

Editor-in-Chief

ISSN (Print): 1574-888X
ISSN (Online): 2212-3946

Review Article

Emerging Role of Mesenchymal Stem Cell-derived Exosomes in Regenerative Medicine

Author(s): Ting Zhao, Feng Sun, Jinwen Liu, Tianyan Ding, Jie She, Fei Mao, Wenrong Xu, Hui Qian and Yongmin Yan*

Volume 14, Issue 6, 2019

Page: [482 - 494] Pages: 13

DOI: 10.2174/1574888X14666190228103230

Price: $65

Abstract

Background: Recent studies have shown the great value of cell therapy over the past few decades. Mesenchymal stem cells (MSCs) have been reported to treat various degenerative diseases not through their differentiation potential but through their paracrine factors of the extracellular vesicle (EV) including exosomes. Exosomes are nanosized (70~150 nm) membrane-bound extracellular vesicles, not only involved in cell-to-cell communication but also in the development of tissue injury repair.

Objective: As more researchers proved the enormous potential of exosomes in the field of repairing damaged tissue currently, it is urgent to explore the concrete mechanism and make exosomes to be a practical treatment tool in clinical medicine. In our study, we analyzed and summarized the work on tissue repair via exosomes in order to give some suggestions about the application of exosomes in clinical reality in the future.

Results: MSC-derived exosomes (MSC-Ex) contain a wide variety of functional proteins, mRNAs, miRNAs and signaling lipids. Compared with their parent cells, MSC-Ex are more stable and can reduce the inherent safety risks in administering viable cells such as the risk of occlusion in microvasculature. MSC-Ex can be used to develop a cell-free exosome-based therapy for regenerative medicine, and may provide an alternative to MSC-based therapy.

Conclusion: This review summarizes the most recent knowledge of therapeutic potential of MSC-Ex in the liver, heart, kidney, bone, brain diseases and cancer, as well as their associated challenges and opportunities.

Keywords: Mesenchymal stem cells, exosomes, tissue, injury, regeneration, repair, liver injury.

[1]
Yang C, Robbins PD. The roles of tumor-derived exosomes in cancer pathogenesis. Clin Dev Immunol 2011; 2011: 842849.
[2]
Yu B, Zhang X, Li X. Exosomes derived from mesenchymal stem cells. Int J Mol Sci 2014; 15: 4142-57.
[3]
Thery C, Witwer KW, Aikawa E, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): A position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles 2018; 7: 1535750.
[4]
Lin J, Li J, Huang B, et al. Exosomes: Novel biomarkers for clinical diagnosis. ScientificWorldJournal 2015; 2015: 657086.
[5]
Baran J, Baj-Krzyworzeka M, Weglarczyk K, et al. Circulating tumour-derived microvesicles in plasma of gastric cancer patients. Cancer Immunol Immunother 2010; 59: 841-50.
[6]
Fu Y, Karbaat L, Wu L, Leijten J, Both SK, Karperien M. Trophic effects of mesenchymal stem cells in tissue regeneration. Tissue Eng Part B Rev 2017; 23: 515-28.
[7]
Furlani D, Ugurlucan M, Ong L, et al. Is the intravascular administration of mesenchymal stem cells safe? Mesenchymal stem cells and intravital microscopy. Microvasc Res 2009; 77: 370-6.
[8]
Gordillo M, Evans T, Gouon-Evans V. Orchestrating liver development. Development 2015; 142: 2094-108.
[9]
Tan CY, Lai RC, Wong W, Dan YY, Lim SK, Ho HK. Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models. Stem Cell Res Ther 2014; 5: 1-14.
[10]
Yan Y, Jiang W, Tan Y, et al. hucMSC Exosome-Derived GPX1 is required for the recovery of hepatic oxidant injury. Mol Ther 2017; 25: 465-79.
[11]
Zhang LT, Fang XQ, Chen QF, et al. Bone marrow-derived mesenchymal stem cells inhibit the proliferation of hepatic stellate cells by inhibiting the transforming growth factor beta pathway. Mol Med Rep 2015; 12: 7227-32.
[12]
An SY, Jang YJ, Lim HJ, et al. Milk Fat Globule-EGF Factor 8. Secreted by mesenchymal stem cells. Protects against liver fibrosis in mice. Gastroenterology 2017; 152: 1174-86.
[13]
Li T, Yan Y, Wang B, et al. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Stem Cells Dev 2013; 22: 845-54.
[14]
Bernstein HS. Cardiac repair and restoration using human embryonic stem cells. Regen Med 2012; 7: 697-712.
[15]
Suzuki E, Fujita D, Takahashi M, Oba S, Nishimatsu H. Therapeutic effects of mesenchymal stem cell-derived exosomes in cardiovascular disease. Adv Exp Med Biol 2017; 998: 179-85.
[16]
Shao L, Zhang Y, Lan B, et al. MiRNA-sequence indicates that mesenchymal stem cells and exosomes have similar mechanism to enhance cardiac repair. Biomed Res Int 2017; 2017: 4150705.
[17]
Emanueli C, Shearn AIU, Angelini GD, Sahoo S. Exosomes and exosomal miRNAs in cardiovascular protection and repair. Vascul Pharmacol 2015; 71: 24-30.
[18]
Zhao Y, Sun X, Cao W, et al. Exosomes derived from human umbilical cord mesenchymal stem cells relieve acute myocardial ischemic injury. Stem Cells Int 2015; 2015: 761643.
[19]
Kang K, Ma R, Cai W, et al. Exosomes Secreted from CXCR4 overexpressing mesenchymal stem cells promote cardioprotection via Akt signaling pathway following myocardial infarction. Stem Cells Int 2015; 2015: 659890.
[20]
Yu B, Kim HW, Gong M, et al. Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection. Int J Cardiol 2015; 182: 349-60.
[21]
Wang X, Gu H, Qin D, et al. Exosomal miR-223 contributes to mesenchymal stem cell-elicited cardioprotection in polymicrobial sepsis. Sci Rep 2015; 5: 13721.
[22]
Ma T, Chen Y, Meng Q, et al. MicroRNA-132. Delivered by mesenchymal stem cell-derived exosomes. Promote angiogenesis in myocardial infarction. Stem Cells Int 2018; 2018: 3290372.
[23]
Lai RC, Yeo RW, Tan KH, Lim SK. Mesenchymal stem cell exosome ameliorates reperfusion injury through proteomic complementation. Regen Med 2013; 8: 197-209.
[24]
Liu L, Jin X, Hu CF, Li R, Zhou Z, Shen CX. Exosomes derived from mesenchymal stem cells rescue myocardial ischaemia/reperfusion injury by inducing cardiomyocyte Autophagy Via AMPK and Akt Pathways. Cell Physiol Biochem 2017; 43: 52-68.
[25]
Morigi M, De Coppi P. Cell therapy for kidney injury: different options and mechanisms--mesenchymal and amniotic fluid stem cells. Nephron, Exp Nephrol 2014; 126: 59.
[26]
Morigi M, Benigni A. Mesenchymal stem cells and kidney repair. Nephrol Dial Transplant 2013; 28: 788-93.
[27]
Bruno S, Grange C, Deregibus MC, et al. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol 2009; 20: 1053-67.
[28]
Bruno S, Grange C, Collino F, et al. Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury. PLoS One 2012; 7: e33115.
[29]
Wang B, Jia H, Zhang B, et al. Pre-incubation with hucMSC-exosomes prevents cisplatin-induced nephrotoxicity by activating autophagy. Stem Cell Res Ther 2017; 8: 75.
[30]
Gatti S, Bruno S, Deregibus MC, et al. Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia-reperfusion-induced acute and chronic kidney injury. Nephrol Dial Transplant 2011; 26: 1474-83.
[31]
He J, Wang Y, Sun S, et al. Bone marrow stem cells-derived microvesicles protect against renal injury in the mouse remnant kidney model. Nephrology (Carlton) 2012; 17: 493-500.
[32]
Reis LA, Borges FT, Simoes MJ, Borges AA, Sinigaglia-Coimbra R, Schor N. Bone marrow-derived mesenchymal stem cells repaired but did not prevent gentamicin-induced acute kidney injury through paracrine effects in rats. PLoS One 2012; 7: e44092.
[33]
Zuckerman SL, Morgan CD, Burks S, et al. Functional and structural traumatic brain injury in equestrian sports: A review of the literature. World Neurosurg 2015; 83: 1098-113.
[34]
Zhang Y, Chopp M, Zhang ZG, et al. Systemic administration of cell-free exosomes generated by human bone marrow derived mesenchymal stem cells cultured under 2D and 3D conditions improves functional recovery in rats after traumatic brain injury. Neurochem Int 2017; 111: 69-81.
[35]
Zhang Y, Chopp M, Meng Y, et al. Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury. J Neurosurg 2015; 122: 856-67.
[36]
Yang Y, Ye Y, Su X, He J, Bai W, He X. MSCs-Derived Exosomes and Neuroinflammation. Neurogenesis and Therapy of Traumatic Brain Injury. Front Cell Neurosci 2017; 11: 55.
[37]
Doeppner TR, Herz J, Gorgens A, et al. Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression. Stem Cells Transl Med 2015; 4: 1131-43.
[38]
Chen KH, Chen CH, Wallace CG, et al. Intravenous administration of xenogenic adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes markedly reduced brain infarct volume and preserved neurological function in rat after acute ischemic stroke. Oncotarget 2016; 7: 74537-56.
[39]
Chang F, Xiong W, Wang D, et al. Facilitation of ultrasonic microvesicles on homing and molecular mechanism of bone marrow mesenchymal stem cells in cerebral infarction patients. Eur Rev Med Pharmacol Sci 2017; 21: 3916-23.
[40]
Xin H, Li Y, Cui Y, Yang JJ, Zhang ZG, Chopp M. Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab 2013; 33: 1711-5.
[41]
Xin H, Li Y, Liu Z, et al. MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles. Stem Cells 2013; 31: 2737-46.
[42]
Xin H, Katakowski M, Wang F, et al. MicroRNA cluster miR-17-92 cluster in exosomes enhance neuroplasticity and functional recovery after stroke in rats. Stroke 2017; 48: 747-53.
[43]
Otero-Ortega L, Gomez de Frutos MC, Laso-Garcia F, et al. Exosomes promote restoration after an experimental animal model of intracerebral hemorrhage. J Cereb Blood Flow Metab 2018; 38: 767-79.
[44]
Katsuda T, Tsuchiya R, Kosaka N, et al. Human adipose tissue-derived mesenchymal stem cells secrete functional neprilysin-bound exosomes. Sci Rep 2013; 3: 1197.
[45]
Zhang S, Chu WC, Lai RC, Lim SK, Hui JH, Toh WS. Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration. Osteoarthritis Cartilage 2016; 24: 2135-40.
[46]
Zhang S, Chuah SJ, Lai RC, Hui JHP, Lim SK, Toh WS. MSC exosomes mediate cartilage repair by enhancing proliferation. attenuating apoptosis and modulating immune reactivity. Biomaterials 2018; 156: 16-27.
[47]
Wang Y, Yu D, Liu Z, et al. Exosomes from embryonic mesenchymal stem cells alleviate osteoarthritis through balancing synthesis and degradation of cartilage extracellular matrix. Stem Cell Res Ther 2017; 8: 189.
[48]
Lai RC, Arslan F, Lee MM, et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res 2010; 4: 214-22.
[49]
Zhang B, Yin Y, Lai RC, Tan SS, Choo AB, Lim SK. Mesenchymal stem cells secrete immunologically active exosomes. Stem Cells Dev 2014; 23: 1233-44.
[50]
Tassew NG, Charish J, Shabanzadeh AP, et al. Exosomes Mediate Mobilization of Autocrine Wnt10b to Promote Axonal Regeneration in the Injured CNS. Cell Rep 2017; 20: 99-111.
[51]
Couch Y, Akbar N, Roodselaar J, et al. Circulating endothelial cell-derived extracellular vesicles mediate the acute phase response and sickness behaviour associated with CNS inflammation. Sci Rep 2017; 7: 9574.
[52]
Huang JH, Yin XM, Xu Y, et al. Systemic administration of exosomes released from mesenchymal stromal cells attenuates apoptosis. inflammation. and promotes angiogenesis after spinal cord injury in rats. J Neurotrauma 2017; 34: 3388-96.
[53]
Yang J, Zhang X, Chen X, Wang L, Yang G. Exosome mediated delivery of miR-124 promotes neurogenesis after ischemia. Mol Ther Nucleic Acids 2017; 7: 278-87.
[54]
Xin H, Wang F, Li Y, et al. Secondary Release of exosomes from astrocytes contributes to the increase in neural plasticity and improvement of functional recovery after stroke in rats treated with exosomes harvested from MicroRNA 133b-overexpressing multipotent mesenchymal stromal cells. Cell Transplant 2017; 26: 243-57.
[55]
Wang L, Pei S, Han L, et al. Mesenchymal stem cell-derived exosomes reduce a1 astrocytes via downregulation of phosphorylated NFkappaB P65 subunit in spinal cord injury. Cell Physiol Biochem 2018; 50: 1535-59.
[56]
Akyurekli C, Le Y, Richardson RB, Fergusson D, Tay J, Allan DS. A systematic review of preclinical studies on the therapeutic potential of mesenchymal stromal cell-derived microvesicles. Stem Cell Rev 2015; 11: 150-60.
[57]
Lener T, Gimona M, Aigner L, et al. Applying extracellular vesicles based therapeutics in clinical trials - an ISEV position paper. J Extracell Vesicles 2015; 4: 30087.
[58]
Lou G, Song X, Yang F, et al. Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma. J Hematol Oncol 2015; 8: 122.
[59]
Haga H, Yan IK, Takahashi K, Matsuda A, Patel T. Extracellular Vesicles from bone marrow-derived mesenchymal stem cells improve survival from lethal hepatic failure in mice. Stem Cells Transl Med 2017; 6: 1262-72.
[60]
Ko SF, Yip HK, Zhen YY, et al. Adipose-derived mesenchymal stem cell exosomes suppress hepatocellular carcinoma growth in a rat model: Apparent diffusion coefficient. Natural Killer T-Cell Responses and Histopathological Features. Stem Cells Int 2015; 2015: 853506.
[61]
Bian S, Zhang L, Duan L, Wang X, Min Y, Yu H. Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model. J Mol Med (Berl) 2014; 92: 387-97.
[62]
Teng X, Chen L, Chen W, Yang J, Yang Z, Shen Z. Mesenchymal stem cell-derived exosomes improve the microenvironment of infarcted myocardium contributing to angiogenesis and anti-inflammation. Cell Physiol Biochem 2015; 37: 2415-24.
[63]
Nakamura Y, Miyaki S, Ishitobi H, et al. Mesenchymal-stem-cell-derived exosomes accelerate skeletal muscle regeneration. FEBS Lett 2015; 589: 1257-65.
[64]
Zou X, Gu D, Xing X, et al. Human mesenchymal stromal cell-derived extracellular vesicles alleviate renal ischemic reperfusion injury and enhance angiogenesis in rats. Am J Transl Res 2016; 8: 4289-99.
[65]
Lin KC, Yip HK, Shao PL, et al. Combination of adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes for protecting kidney from acute ischemia-reperfusion injury. Int J Cardiol 2016; 216: 173-85.
[66]
Yuan X, Li D, Chen X, et al. Extracellular vesicles from human-induced pluripotent stem cell-derived mesenchymal stromal cells (hiPSC-MSCs) protect against renal ischemia/reperfusion injury via delivering specificity protein (SP1) and transcriptional activating of sphingosine kinase 1 and inhibiting necroptosis. Cell Death Dis 2017; 8: 3200.
[67]
Tomasoni S, Longaretti L, Rota C, et al. Transfer of growth factor receptor mRNA via exosomes unravels the regenerative effect of mesenchymal stem cells. Stem Cells Dev 2013; 22: 772-80.
[68]
Lindoso RS, Collino F, Bruno S, et al. Extracellular vesicles released from mesenchymal stromal cells modulate miRNA in renal tubular cells and inhibit ATP depletion injury. Stem Cells Dev 2014; 23: 1809-19.
[69]
Zou X, Zhang G, Cheng Z, et al. Microvesicles derived from human Wharton’s Jelly mesenchymal stromal cells ameliorate renal ischemia-reperfusion injury in rats by suppressing CX3CL1. Stem Cell Res Ther 2014; 5: 40.
[70]
Collino F, Bruno S, Incarnato D, et al. AKI Recovery induced by mesenchymal stromal cell-derived extracellular vesicles carrying MicroRNAs. J Am Soc Nephrol 2015; 26: 2349-60.
[71]
Hu B, Chen S, Zou M, He Z, Shao S, Liu B. Effect of extracellular vesicles on neural functional recovery and immunologic suppression after rat cerebral apoplexy. Cell Physiol Biochem 2016; 40: 155-62.
[72]
Farinazzo A, Turano E, Marconi S, Bistaffa E, Bazzoli E, Bonetti B. Murine adipose-derived mesenchymal stromal cell vesicles: In vitro clues for neuroprotective and neuroregenerative approaches. Cytotherapy 2015; 17: 571-8.
[73]
Ophelders DR, Wolfs TG, Jellema RK, et al. Mesenchymal stromal cell-derived extracellular vesicles protect the fetal brain after hypoxia-ischemia. Stem Cells Transl Med 2016; 5: 754-63.
[74]
Lee C, Mitsialis SA, Aslam M, et al. Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation 2012; 126: 2601-11.
[75]
Aliotta JM, Pereira M, Wen S, et al. Exosomes induce and reverse monocrotaline-induced pulmonary hypertension in mice. Cardiovasc Res 2016; 110: 319-30.
[76]
Choi M, Ban T, Rhim T. Therapeutic use of stem cell transplantation for cell replacement or cytoprotective effect of microvesicle released from mesenchymal stem cell. Mol Cells 2014; 37: 133-9.
[77]
Zhang J, Guan J, Niu X, et al. Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis. J Transl Med 2015; 13: 49.
[78]
Zhang B, Wang M, Gong A, et al. HucMSC-exosome mediated-Wnt4 signaling is required for cutaneous wound healing. Stem Cells 2015; 33: 2158-68.
[79]
Zhang HC, Liu XB, Huang S, et al. Microvesicles derived from human umbilical cord mesenchymal stem cells stimulated by hypoxia promote angiogenesis both in vitro and in vivo. Stem Cells Dev 2012; 21: 3289-97.

Rights & Permissions Print Export Cite as
© 2024 Bentham Science Publishers | Privacy Policy