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Exosomes and regenerative medicine: state of the art and perspectives

  • Hui Jing
    Affiliations
    Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Xiaomin He
    Correspondence
    Reprint requests: Jinghao ZhengXiaomin He, Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, 1678 Dongfang Road, Shanghai 200127, China;
    Affiliations
    Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
    Search for articles by this author
  • Jinghao Zheng
    Correspondence
    Reprint requests: Jinghao ZhengXiaomin He, Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, 1678 Dongfang Road, Shanghai 200127, China;
    Affiliations
    Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
    Search for articles by this author
Published:February 04, 2018DOI:https://doi.org/10.1016/j.trsl.2018.01.005
      Exosomes have attracted the attention of the scientific community in recent years due to their widespread distribution, their possible functions as biomarkers of disease, and their great potential to be applied as therapeutic agents. Exosomes carry proteins and nucleic acids that can facilitate their uptake by distant target cells through endocytosis, such that exosomes could be targeted to a specific cell or cells to enhance or interfere with specific biological processes. This review will mainly focus on their roles in tissue repair and regenerative processes. Exosomal engineering and their potential applications in tissue regeneration are also reviewed here as an outlook for future research.

      Abbreviations:

      adMSCs (adipose-derived MSCs), AIS (acute ischemic stroke), AKI (acute kidney injury), AMI (acute myocardial infarction), BMP-7 (bone morphogenetic protein 7), CCl4 (carbon tetrachloride), CDCs (cardiosphere-derived cells), CM (conditioned medium), CPCs (cardiac progenitor cells), CSCs (cardiac stem cells), DM (diabetes mellitus), DPSCs (dental pulp stem cells), ECs (endothelial cells), ECFCs (endothelial colony-forming cells), EPCs (endothelial progenitor cells), EGFR (epidermal growth factor receptor), EVs (extracellular vesicles), GPX1 (glutathione peroxidase1), hASCs (human adipose-derived stem cells), hBMSCs (human bone marrow mesenchymal stem cells), HCV (hepatitis C virus), hiPSC-MSCs (human-induced pluripotent stem cell-derived mesenchymal stromal cells), hMSCs (human bone marrow-derived stromal cells), hSkMs (human skeletal myoblasts), hSMMSCs (human synovial membrane MSCs), hUCMSCs (human umbilical cord mesenchymal stem cells), hUSCs (human urine-derived stem cells), IGF-1R (insulin-like growth factor-1 receptor), IL-1β (interleukin-1β), iMSCs (induced pluripotent stem cell-derived MSCs), MAPK (mitogen-activated protein kinase), mES (mouse embryonic stem cells), MSCs (mesenchymal stem cell), mRNAs (messenger RNAs), miRNAs (microRNAs), RGCs (retinal ganglion cells), PF (pericardial fluid), PRP (platelet-rich plasma), RARβ (retinoic acid receptor β), SCs (Schwann cells), SCIs (spinal cord injuries), SD rats (Sprague Dawley rats), siRNA (short-interfering RNA), SK2 (sphingosine kinase 2), TBI (traumatic brain injury), TGF-β1 (transforming growth factor-β1), TNF-α (tumor necrosis factor α), USCs (urine-derived stem cells), VEGF (vascular endothelial growth factor)
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      References

        • Muller E.
        • Wang W.
        • Qiao W.
        • et al.
        Distinguishing autocrine and paracrine signals in hematopoietic stem cell culture using a biofunctional microcavity platform.
        Sci Rep. 2016; 6: 31951
        • Cho K.I.
        • Yoon D.
        • Qiu S.
        • et al.
        Loss of Ranbp2 in motor neurons causes the disruption of nucleocytoplasmic and chemokine signaling and proteostasis of hnRNPH3 and Mmp28, and the development of amyotrophic lateral sclerosis (ALS)-like syndromes.
        Dis Model Mech. 2017; 10: 559-579
        • Civitarese R.A.
        • Kapus A.
        • McCulloch C.A.
        • Connelly K.A.
        Role of integrins in mediating cardiac fibroblast-cardiomyocyte cross talk: a dynamic relationship in cardiac biology and pathophysiology.
        Basic Res Cardiol. 2017; 112: 6
        • Plotnikov E.Y.
        • Silachev D.N.
        • Popkov V.A.
        • et al.
        Intercellular signalling cross-talk: to kill, to heal and to rejuvenate.
        Heart Lung Circ. 2017; 26: 648-659
        • Parascandolo A.
        • Rappa F.
        • Cappello F.
        • et al.
        Extracellular superoxide dismutase expression in papillary thyroid cancer mesenchymal stem/stromal cells modulates cancer cell growth and migration.
        Sci Rep. 2017; 7: 41416
        • Wang J.
        • Sun B.
        • Tian L.
        • et al.
        Evaluation of the potential of rhTGF- beta3 encapsulated P(LLA-CL)/collagen nanofibers for tracheal cartilage regeneration using mesenchymal stems cells derived from Wharton's jelly of human umbilical cord.
        Mater Sci Eng C Mater Biol Appl. 2017; 70: 637-645
        • Blondiaux E.
        • Pidial L.
        • Autret G.
        • et al.
        Bone marrow-derived mesenchymal stem cell-loaded fibrin patches act as a reservoir of paracrine factors in chronic myocardial infarction.
        J Tissue Eng Regen Med. 2017; 11: 3417-3427
        • Zhang Y.
        • Yu M.
        • Dai M.
        • et al.
        miR-450a-5p within rat adipose tissue exosome-like vesicles promotes adipogenic differentiation by targeting WISP2.
        J Cell Sci. 2017; 130: 1158-1168
        • Collino F.
        • Pomatto M.
        • Bruno S.
        • et al.
        Exosome and microvesicle-enriched fractions isolated from mesenchymal stem cells by gradient separation showed different molecular signatures and functions on renal tubular epithelial cells.
        Stem Cell Rev. 2017; 13: 226-243
        • Goloviznina N.A.
        • Verghese S.C.
        • Yoon Y.M.
        • Taratula O.
        • Marks D.L.
        • Kurre P.
        Mesenchymal stromal cell-derived extracellular vesicles promote myeloid-biased multipotent hematopoietic progenitor expansion via toll-like receptor engagement.
        J Biol Chem. 2016; 291: 24607-24617
        • Lee M.
        • Ban J.J.
        • Kim K.Y.
        • et al.
        Adipose-derived stem cell exosomes alleviate pathology of amyotrophic lateral sclerosis in vitro.
        Biochem Biophys Res Commun. 2016; 479: 434-439
        • Furuta T.
        • Miyaki S.
        • Ishitobi H.
        • et al.
        Mesenchymal stem cell-derived exosomes promote fracture healing in a mouse model.
        Stem Cells Transl Med. 2016; 5: 1620-1630
        • Johnstone R.M.
        • Adam M.
        • Hammond J.R.
        • Orr L.
        • Turbide C.
        Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes).
        J Biol Chem. 1987; 262: 9412-9420
        • Geminard C.
        • Nault F.
        • Johnstone R.M.
        • Vidal M.
        Characteristics of the interaction between Hsc70 and the transferrin receptor in exosomes released during reticulocyte maturation.
        J Biol Chem. 2001; 276: 9910-9916
        • Johnstone R.M.
        Cleavage of the transferrin receptor by human granulocytes: differential proteolysis of the exosome-bound TFR.
        J Cell Physiol. 1996; 168: 333-345
        • Katsiougiannis S.
        • Chia D.
        • Kim Y.
        • Singh R.P.
        • Wong D.T.
        Saliva exosomes from pancreatic tumor-bearing mice modulate NK cell phenotype and antitumor cytotoxicity.
        FASEB J. 2017; 31: 998-1010
        • Hock A.
        • Miyake H.
        • Li B.
        • et al.
        Breast milk-derived exosomes promote intestinal epithelial cell growth.
        J Pediatr Surg. 2017; 52: 755-759
        • Xiao G.Y.
        • Cheng C.C.
        • Chiang Y.S.
        • Cheng W.T.
        • Liu I.H.
        • Wu S.C.
        Exosomal miR-10a derived from amniotic fluid stem cells preserves ovarian follicles after chemotherapy.
        Sci Rep. 2016; 6: 23120
        • An M.
        • Lohse I.
        • Tan Z.
        • et al.
        Quantitative proteomic analysis of serum exosomes from patients with locally advanced pancreatic cancer undergoing chemoradiotherapy.
        J Proteome Res. 2017; 16: 1763-1772
        • Domenyuk V.
        • Zhong Z.
        • Stark A.
        • et al.
        Plasma exosome profiling of cancer patients by a next generation systems biology approach.
        Sci Rep. 2017; 7: 42741
        • Sun H.
        • Yao W.
        • Tang Y.
        • et al.
        Urinary exosomes as a novel biomarker for evaluation of alpha-lipoic acid's protective effect in early diabetic nephropathy.
        J Clin Lab Anal. 2017; https://doi.org/10.1002/jcla.22129
        • Lee M.J.
        • Park D.H.
        • Kang J.H.
        Exosomes as the source of biomarkers of metabolic diseases.
        Ann Pediatr Endocrinol Metab. 2016; 21: 119-125
        • Mitchell P.
        • Tollervey D.
        Finding the exosome.
        Adv Exp Med Biol. 2010; 702: 1-8
        • Kastelowitz N.
        • Yin H.
        Exosomes and microvesicles: identification and targeting by particle size and lipid chemical probes.
        Chembiochem. 2014; 15: 923-928
        • Wang D.
        • Sun W.
        Urinary extracellular microvesicles: isolation methods and prospects for urinary proteome.
        Proteomics. 2014; 14: 1922-1932
        • Stahl P.D.
        • Barbieri M.A.
        Multivesicular bodies and multivesicular endosomes: the “ins and outs” of endosomal traffic.
        Sci STKE. 2002; 2002 (pe32)
        • Montecalvo A.
        • Larregina A.T.
        • Morelli A.E.
        Methods of purification of CTL-derived exosomes.
        Methods Mol Biol. 2014; 1186: 87-102
        • Rog T.
        • Orlowski A.
        • Llorente A.
        • et al.
        Interdigitation of long-chain sphingomyelin induces coupling of membrane leaflets in a cholesterol dependent manner.
        Biochim Biophys Acta. 2016; 1858: 281-288
        • Simbari F.
        • McCaskill J.
        • Coakley G.
        • et al.
        Plasmalogen enrichment in exosomes secreted by a nematode parasite versus those derived from its mouse host: implications for exosome stability and biology.
        J Extracell Vesicles. 2016; 5: 30741
        • Zhou Q.
        • Rahimian A.
        • Son K.
        • Shin D.S.
        • Patel T.
        • Revzin A.
        Development of an aptasensor for electrochemical detection of exosomes.
        Methods. 2016; 97: 88-93
        • Oliveira-Rodriguez M.
        • Lopez-Cobo S.
        • Reyburn H.T.
        • et al.
        Development of a rapid lateral flow immunoassay test for detection of exosomes previously enriched from cell culture medium and body fluids.
        J Extracell Vesicles. 2016; 5: 31803
        • Lai X.
        • Wang M.
        • McElyea S.D.
        • Sherman S.
        • House M.
        • Korc M.
        A microRNA signature in circulating exosomes is superior to exosomal glypican-1 levels for diagnosing pancreatic cancer.
        Cancer Lett. 2017; 393: 86-93
        • Mead B.
        • Tomarev S.
        Bone marrow-derived mesenchymal stem cells-derived exosomes promote survival of retinal ganglion cells through miRNA-dependent mechanisms.
        Stem Cells Transl Med. 2017; 6: 1273-1285
        • Li J.
        • Chen Y.
        • Guo X.
        • et al.
        GPC1 exosome and its regulatory miRNAs are specific markers for the detection and target therapy of colorectal cancer.
        J Cell Mol Med. 2017; 21: 838-847
        • Teng Y.
        • Ren Y.
        • Hu X.
        • et al.
        MVP-mediated exosomal sorting of miR-193a promotes colon cancer progression.
        Nat Commun. 2017; 8: 14448
        • Lim J.H.
        • Song M.K.
        • Cho Y.
        • Kim W.
        • Han S.O.
        • Ryu J.C.
        Comparative analysis of microRNA and mRNA expression profiles in cells and exosomes under toluene exposure.
        Toxicol In Vitro. 2017; 41: 92-101
        • Beltrami C.
        • Besnier M.
        • Shantikumar S.
        • et al.
        Human pericardial fluid contains exosomes enriched with cardiovascular-expressed MicroRNAs and promotes therapeutic angiogenesis.
        Mol Ther. 2017; 25: 679-693
        • Yu X.
        • Odenthal M.
        • Fries J.W.
        Exosomes as miRNA carriers: formation-function-future.
        Int J Mol Sci. 2016; 17
        • Khoontawad J.
        • Pairojku C.
        • Rucksaken R.
        • et al.
        Differential protein expression marks the transition from infection with Opisthorchis viverrini to cholangiocarcinoma.
        Mol Cell Proteomics. 2017; 16: 911-923
        • Cao X.Y.
        • Lu J.M.
        • Zhao Z.Q.
        • et al.
        MicroRNA biomarkers of Parkinson's disease in serum exosome-like microvesicles.
        Neurosci Lett. 2017; 644: 94-99
        • Cho Y.E.
        • Kim S.H.
        • Lee B.H.
        • Baek M.C.
        Circulating plasma and exosomal microRNAs as indicators of drug-induced organ injury in rodent models.
        Biomol Ther (Seoul). 2017; 25: 367-373
        • Panich T.
        • Chancharoenthana W.
        • Somparn P.
        • Issara-Amphorn J.
        • Hirankarn N.
        • Leelahavanichkul A.
        Urinary exosomal activating transcriptional factor 3 as the early diagnostic biomarker for sepsis-induced acute kidney injury.
        BMC Nephrol. 2017; 18: 10
        • Rong L.
        • Li R.
        • Li S.
        • Luo R.
        Immunosuppression of breast cancer cells mediated by transforming growth factor-beta in exosomes from cancer cells.
        Oncol Lett. 2016; 11: 500-504
        • Hu Y.
        • Li D.
        • Wu A.
        • et al.
        TWEAK-stimulated macrophages inhibit metastasis of epithelial ovarian cancer via exosomal shuttling of microRNA.
        Cancer Lett. 2017; 393: 60-67
        • Min H.
        • Sun X.
        • Yang X.
        • et al.
        Exosomes derived from irradiated esophageal carcinoma-infiltrating T cells promote metastasis by inducing the epithelial-mesenchymal transition in esophageal cancer cells.
        Pathol Oncol Res. 2018; 24: 11-18
        • Momen-Heravi F.
        • Bala S.
        • Kodys K.
        • Szabo G.
        Exosomes derived from alcohol-treated hepatocytes horizontally transfer liver specific miRNA-122 and sensitize monocytes to LPS.
        Sci Rep. 2015; 5: 9991
        • Sukma Dewi I.
        • Celik S.
        • Karlsson A.
        • et al.
        Exosomal miR-142-3p is increased during cardiac allograft rejection and augments vascular permeability through down-regulation of endothelial RAB11FIP2 expression.
        Cardiovasc Res. 2017; 113: 440-452
        • Ellwanger J.H.
        • Crovella S.
        • Dos Reis E.C.
        • Pontillo A.
        • Chies J.A.
        Exosomes are possibly used as a tool of immune regulation during the dendritic cell-based immune therapy against HIV-I.
        Med Hypotheses. 2016; 95: 67-70
        • Toh W.S.
        • Lai R.C.
        • Hui J.H.
        • Lim S.K.
        MSC exosome as a cell-free MSC therapy for cartilage regeneration: implications for osteoarthritis treatment.
        Semin Cell Dev Biol. 2017; 67: 56-64
        • Prathipati P.
        • Nandi S.S.
        • Mishra P.K.
        Stem cell-derived exosomes, autophagy, extracellular matrix turnover, and miRNAs in cardiac regeneration during stem cell therapy.
        Stem Cell Rev. 2017; 13: 79-91
        • Pashoutan Sarvar D.
        • Shamsasenjan K.
        • Akbarzadehlaleh P.
        Mesenchymal stem cell-derived exosomes: new opportunity in cell-free therapy.
        Adv Pharm Bull. 2016; 6: 293-299
        • Liu S.
        • Liu D.
        • Chen C.
        • et al.
        MSC transplantation improves osteopenia via epigenetic regulation of notch signaling in lupus.
        Cell Metab. 2015; 22: 606-618
        • Tan S.S.
        • Yin Y.
        • Lee T.
        • et al.
        Therapeutic MSC exosomes are derived from lipid raft microdomains in the plasma membrane.
        J Extracell Vesicles. 2013; 2
        • Park S.
        • Choi Y.
        • Jung N.
        • et al.
        Myogenic differentiation potential of human tonsil-derived mesenchymal stem cells and their potential for use to promote skeletal muscle regeneration.
        Int J Mol Med. 2016; 37: 1209-1220
        • Iwai S.
        • Sakonju I.
        • Okano S.
        • et al.
        Impact of ex vivo administration of mesenchymal stem cells on the function of kidney grafts from cardiac death donors in rat.
        Transplant Proc. 2014; 46: 1578-1584
        • Merino A.
        • Ripoll E.
        • de Ramon L.
        • et al.
        The timing of immunomodulation induced by mesenchymal stromal cells determines the outcome of the graft in experimental renal allotransplantation.
        Cell Transplant. 2017; 26: 1017-1030
        • Aharon A.
        • Tamari T.
        • Brenner B.
        Monocyte-derived microparticles and exosomes induce procoagulant and apoptotic effects on endothelial cells.
        Thromb Haemost. 2008; 100: 878-885
        • Li F.
        • Wang Y.
        • Lin L.
        • et al.
        Mast cell-derived exosomes promote Th2 cell differentiation via OX40L-OX40 ligation.
        J Immunol Res. 2016; 2016 (3623898)
        • Liu H.
        • Gao W.
        • Yuan J.
        • et al.
        Exosomes derived from dendritic cells improve cardiac function via activation of CD4(+) T lymphocytes after myocardial infarction.
        J Mol Cell Cardiol. 2016; 91: 123-133
        • Ji Q.
        • Ji Y.
        • Peng J.
        • et al.
        Increased brain-specific MiR-9 and MiR-124 in the serum exosomes of acute ischemic stroke patients.
        PLoS ONE. 2016; 11 (e0163645)
        • Frohlich D.
        • Kuo W.P.
        • Fruhbeis C.
        • et al.
        Multifaceted effects of oligodendroglial exosomes on neurons: impact on neuronal firing rate, signal transduction and gene regulation.
        Philos Trans R Soc Lond B Biol Sci. 2014; 369
        • Xin H.
        • Li Y.
        • Buller B.
        • et al.
        Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth.
        Stem Cells. 2012; 30: 1556-1564
        • Takeda Y.S.
        • Xu Q.
        Neuronal differentiation of human mesenchymal stem cells using exosomes derived from differentiating neuronal cells.
        PLoS ONE. 2015; 10 (e0135111)
        • Zhang Y.
        • Chopp M.
        • Zhang Z.G.
        • 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
        • Zhang Y.
        • Chopp M.
        • Liu X.S.
        • et al.
        Exosomes derived from mesenchymal stromal cells promote axonal growth of cortical neurons.
        Mol Neurobiol. 2017; 54: 2659-2673
        • El Bassit G.
        • Patel R.S.
        • Carter G.
        • et al.
        MALAT1 in human adipose stem cells modulates survival and alternative splicing of PKCdeltaII in HT22 cells.
        Endocrinology. 2017; 158 (en20161819): 183-195
        • Lopez-Verrilli M.A.
        • Picou F.
        • Court F.A.
        Schwann cell-derived exosomes enhance axonal regeneration in the peripheral nervous system.
        Glia. 2013; 61: 1795-1806
        • Goncalves M.B.
        • Malmqvist T.
        • Clarke E.
        • et al.
        Neuronal RARbeta signaling modulates PTEN activity directly in neurons and via exosome transfer in astrocytes to prevent glial scar formation and induce spinal cord regeneration.
        J Neurosci. 2015; 35: 15731-15745
        • Ibrahim A.G.
        • Cheng K.
        • Marban E.
        Exosomes as critical agents of cardiac regeneration triggered by cell therapy.
        Stem Cell Reports. 2014; 2: 606-619
        • 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: 2415-2424
        • Zhang Z.
        • Yang J.
        • Yan W.
        • Li Y.
        • Shen Z.
        • Asahara T.
        Pretreatment of cardiac stem cells with exosomes derived from mesenchymal stem cells enhances myocardial repair.
        J Am Heart Assoc. 2016; 5
        • Khan M.
        • Nickoloff E.
        • Abramova T.
        • et al.
        Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function following myocardial infarction.
        Circ Res. 2015; 117: 52-64
        • 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
        • Vicencio J.M.
        • Yellon D.M.
        • Sivaraman V.
        • et al.
        Plasma exosomes protect the myocardium from ischemia-reperfusion injury.
        J Am Coll Cardiol. 2015; 65: 1525-1536
        • Agarwal U.
        • George A.
        • Bhutani S.
        • et al.
        Experimental, systems, and computational approaches to understanding the MicroRNA-mediated reparative potential of cardiac progenitor cell-derived exosomes from pediatric patients.
        Circ Res. 2017; 120: 701-712
        • Momen-Heravi F.
        • Saha B.
        • Kodys K.
        • Catalano D.
        • Satishchandran A.
        • Szabo G.
        Increased number of circulating exosomes and their microRNA cargos are potential novel biomarkers in alcoholic hepatitis.
        J Transl Med. 2015; 13: 261
        • Thulin P.
        • Hornby R.J.
        • Auli M.
        • et al.
        A longitudinal assessment of miR-122 and GLDH as biomarkers of drug-induced liver injury in the rat.
        Biomarkers. 2016; : 1-9
        • Povero D.
        • Eguchi A.
        • Li H.
        • et al.
        Circulating extracellular vesicles with specific proteome and liver microRNAs are potential biomarkers for liver injury in experimental fatty liver disease.
        PLoS ONE. 2014; 9 (e113651)
        • Nojima H.
        • Freeman C.M.
        • Schuster R.M.
        • et al.
        Hepatocyte exosomes mediate liver repair and regeneration via sphingosine-1-phosphate.
        J Hepatol. 2016; 64: 60-68
        • Tan C.Y.
        • Lai R.C.
        • Wong W.
        • Dan Y.Y.
        • Lim S.K.
        • Ho H.K.
        Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models.
        Stem Cell Res Ther. 2014; 5: 76
        • 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: 465-479
        • Nong K.
        • Wang W.
        • Niu X.
        • et al.
        Hepatoprotective effect of exosomes from human-induced pluripotent stem cell-derived mesenchymal stromal cells against hepatic ischemia-reperfusion injury in rats.
        Cytotherapy. 2016; 18: 1548-1559
        • 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: 772-780
        • Zhou Y.
        • Xu H.
        • Xu W.
        • et al.
        Exosomes released by human umbilical cord mesenchymal stem cells protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in vitro.
        Stem Cell Res Ther. 2013; 4: 34
        • Borges F.T.
        • Melo S.A.
        • Ozdemir B.C.
        • et al.
        TGF-beta1-containing exosomes from injured epithelial cells activate fibroblasts to initiate tissue regenerative responses and fibrosis.
        J Am Soc Nephrol. 2013; 24: 385-392
        • Burger D.
        • Vinas J.L.
        • Akbari S.
        • et al.
        Human endothelial colony-forming cells protect against acute kidney injury: role of exosomes.
        Am J Pathol. 2015; 185: 2309-2323
        • Vinas J.L.
        • Burger D.
        • Zimpelmann J.
        • et al.
        Transfer of microRNA-486-5p from human endothelial colony forming cell-derived exosomes reduces ischemic kidney injury.
        Kidney Int. 2016; 90: 1238-1250
        • Wang B.
        • Yao K.
        • Huuskes B.M.
        • et al.
        Mesenchymal stem cells deliver exogenous MicroRNA-let7c via exosomes to attenuate renal fibrosis.
        Mol Ther. 2016; 24: 1290-1301
        • Jiang Z.Z.
        • Liu Y.M.
        • Niu X.
        • et al.
        Exosomes secreted by human urine-derived stem cells could prevent kidney complications from type I diabetes in rats.
        Stem Cell Res Ther. 2016; 7: 24
        • Salem K.Z.
        • Moschetta M.
        • Sacco A.
        • et al.
        Exosomes in tumor angiogenesis.
        Methods Mol Biol. 2016; 1464: 25-34
        • Wang Z.
        • Chen J.Q.
        • Liu J.L.
        • Tian L.
        Exosomes in tumor microenvironment: novel transporters and biomarkers.
        J Transl Med. 2016; 14: 297
        • Gopal S.K.
        • Greening D.W.
        • Rai A.
        • et al.
        Extracellular vesicles: their role in cancer biology and epithelial-mesenchymal transition.
        Biochem J. 2017; 474: 21-45
        • Liang X.
        • Zhang L.
        • Wang S.
        • Han Q.
        • Zhao R.C.
        Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a.
        J Cell Sci. 2016; 129: 2182-2189
        • Yuan H.
        • Guan J.
        • Zhang J.
        • Zhang R.
        • Li M.
        Exosomes secreted by human urine-derived stem cells accelerate skin wound healing by promoting angiogenesis in rat.
        Cell Biol Int. 2016; https://doi.org/10.1002/cbin.10615
        • Li X.
        • Liu L.
        • Yang J.
        • et al.
        Exosome derived from human umbilical cord mesenchymal stem cell mediates MiR-181c attenuating burn-induced excessive inflammation.
        EBioMedicine. 2016; 8: 72-82
        • Burns C.
        • Hall S.T.
        • Smith R.
        • Blackwell C.
        Cytokine levels in late pregnancy: are female infants better protected against inflammation?.
        Front Immunol. 2015; 6: 318
        • Guo S.X.
        • Jin Y.Y.
        • Fang Q.
        • et al.
        Beneficial effects of hydrogen-rich saline on early burn-wound progression in rats.
        PLoS ONE. 2015; 10 (e0124897)
        • Zhao B.
        • Zhang Y.
        • Han S.
        • et al.
        Exosomes derived from human amniotic epithelial cells accelerate wound healing and inhibit scar formation.
        J Mol Histol. 2017; 48: 121-132
        • Zhao B.
        • Wu G.F.
        • Zhang Y.J.
        • et al.
        [Effects of human amniotic epithelial stem cells-derived exosomes on healing of wound with full-thickness skin defect in rats].
        Zhonghua Shao Shang Za Zhi. 2017; 33: 18-23
        • Zhang J.
        • Chen C.
        • Hu B.
        • et al.
        Exosomes derived from human endothelial progenitor cells accelerate cutaneous wound healing by promoting angiogenesis through Erk1/2 signaling.
        Int J Biol Sci. 2016; 12: 1472-1487
        • Guo S.C.
        • Tao S.C.
        • Yin W.J.
        • Qi X.
        • Yuan T.
        • Zhang C.Q.
        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: 81-96
        • Pu C.M.
        • Liu C.W.
        • Liang C.J.
        • et al.
        Adipose-derived stem cells protect skin flaps against ischemia/reperfusion injury via interleukin-6 expression.
        J Invest Dermatol. 2017; 137: 1353-1362
        • Han K.Y.
        • Tran J.A.
        • Chang J.H.
        • Azar D.T.
        • Zieske J.D.
        Potential role of corneal epithelial cell-derived exosomes in corneal wound healing and neovascularization.
        Sci Rep. 2017; 7: 40548
        • Zhang B.
        • Wu X.
        • Zhang X.
        • et al.
        Human umbilical cord mesenchymal stem cell exosomes enhance angiogenesis through the Wnt4/beta-catenin pathway.
        Stem Cells Transl Med. 2015; 4: 513-522
        • Zhang J.
        • Liu X.
        • Li H.
        • et al.
        Exosomes/tricalcium phosphate combination scaffolds can enhance bone regeneration by activating the PI3K/Akt signaling pathway.
        Stem Cell Res Ther. 2016; 7: 136
        • Qi X.
        • Zhang J.
        • Yuan H.
        • et al.
        Exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells repair critical-sized bone defects through enhanced angiogenesis and osteogenesis in osteoporotic rats.
        Int J Biol Sci. 2016; 12: 836-849
        • Zhang S.
        • Chu W.C.
        • Lai R.C.
        • Lim S.K.
        • Hui J.H.
        • Toh W.S.
        Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration.
        Osteoarthritis Cartilage. 2016; 24: 2135-2140
        • Zhu Y.
        • Wang Y.
        • Zhao B.
        • et al.
        Comparison of exosomes secreted by induced pluripotent stem cell-derived mesenchymal stem cells and synovial membrane-derived mesenchymal stem cells for the treatment of osteoarthritis.
        Stem Cell Res Ther. 2017; 8: 64
        • Nakamura Y.
        • Miyaki S.
        • Ishitobi H.
        • et al.
        Mesenchymal-stem-cell-derived exosomes accelerate skeletal muscle regeneration.
        FEBS Lett. 2015; 589: 1257-1265
        • Choi J.S.
        • Yoon H.I.
        • Lee K.S.
        • et al.
        Exosomes from differentiating human skeletal muscle cells trigger myogenesis of stem cells and provide biochemical cues for skeletal muscle regeneration.
        J Control Release. 2016; 222: 107-115
        • Huang C.C.
        • Narayanan R.
        • Alapati S.
        • Ravindran S.
        Exosomes as biomimetic tools for stem cell differentiation: applications in dental pulp tissue regeneration.
        Biomaterials. 2016; 111: 103-115
        • Ellis C.
        • Ramzy A.
        • Kieffer T.J.
        Regenerative medicine and cell-based approaches to restore pancreatic function.
        Nat Rev Gastroenterol Hepatol. 2017; 14: 612-628
        • Oh K.
        • Kim S.R.
        • Kim D.K.
        • et al.
        In vivo differentiation of therapeutic insulin-producing cells from bone marrow cells via extracellular vesicle-mimetic nanovesicles.
        ACS Nano. 2015; 9: 11718-11727
        • Mikamori M.
        • Yamada D.
        • Eguchi H.
        • et al.
        MicroRNA-155 controls exosome synthesis and promotes gemcitabine resistance in pancreatic ductal adenocarcinoma.
        Sci Rep. 2017; 7: 42339
        • Rayner S.
        • Bruhn S.
        • Vallhov H.
        • Andersson A.
        • Billmyre R.B.
        • Scheynius A.
        Identification of small RNAs in extracellular vesicles from the commensal yeast Malassezia sympodialis.
        Sci Rep. 2017; 7: 39742
        • Jiang J.
        • Kao C.Y.
        • Papoutsakis E.T.
        How do megakaryocytic microparticles target and deliver cargo to alter the fate of hematopoietic stem cells?.
        J Control Release. 2017; 247: 1-18
        • Sun D.
        • Zhuang X.
        • Xiang X.
        • et al.
        A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes.
        Mol Ther. 2010; 18: 1606-1614
        • Ohno S.I.
        • Takanashi M.
        • Sudo K.
        • et al.
        Systemically injected exosomes targeted to EGFR deliver antitumor MicroRNA to breast cancer cells.
        Mol Ther. 2013; 21: 185-191
        • Huang Z.
        • Feng Y.
        Exosomes derived from hypoxic colorectal cancer cells promotes angiogenesis through Wnt4 induced beta-catenin signaling in endothelial cells.
        Oncol Res. 2016; 25: 651-661
        • Ti D.
        • Hao H.
        • Tong C.
        • et al.
        LPS-preconditioned mesenchymal stromal cells modify macrophage polarization for resolution of chronic inflammation via exosome-shuttled let-7b.
        J Transl Med. 2015; 13: 308
        • Zhuang X.
        • Xiang X.
        • Grizzle W.
        • et al.
        Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain.
        Mol Ther. 2011; 19: 1769-1779
        • Alvarez-Erviti L.
        • Seow Y.
        • Yin H.
        • Betts C.
        • Lakhal S.
        • Wood M.J.
        Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes.
        Nat Biotechnol. 2011; 29: 341-345
        • de Rivero Vaccari J.P.
        • Brand 3rd, F.
        • Adamczak S.
        • et al.
        Exosome-mediated inflammasome signaling after central nervous system injury.
        J Neurochem. 2016; 136: 39-48
        • Kowal J.
        • Arras G.
        • Colombo M.
        • et al.
        Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes.
        Proc Natl Acad Sci USA. 2016; 113: E968-E977
        • Santana S.M.
        • Antonyak M.A.
        • Cerione R.A.
        • Kirby B.J.
        Microfluidic isolation of cancer-cell-derived microvesicles from heterogeneous extracellular shed vesicle populations.
        Biomed Microdevices. 2014; 16: 869-877
        • Garcia N.A.
        • Ontoria-Oviedo I.
        • Gonzalez-King H.
        • Diez-Juan A.
        • Sepulveda P.
        Glucose starvation in cardiomyocytes enhances exosome secretion and promotes angiogenesis in endothelial cells.
        PLoS ONE. 2015; 10 (e0138849)
        • Ramakrishnaiah V.
        • Thumann C.
        • Fofana I.
        • et al.
        Exosome-mediated transmission of hepatitis C virus between human hepatoma Huh7.5 cells.
        Proc Natl Acad Sci USA. 2013; 110: 13109-13113