Mesenchymal stromal cell-derived exosomes in cardiac regeneration and repair DOI Creative Commons
Si-Jia Sun, Rui Wei, Fei Li

et al.

Stem Cell Reports, Journal Year: 2021, Volume and Issue: 16(7), P. 1662 - 1673

Published: June 10, 2021

Mesenchymal stromal cell (MSC)-derived exosomes play a promising role in regenerative medicine. Their trophic and immunomodulatory potential has made them candidate for cardiac regeneration repair. Numerous studies have demonstrated that MSC-derived can replicate the anti-inflammatory, anti-apoptotic, pro-angiogenic anti-fibrotic effects of their parent cells are considered substitute cell-based therapies. In addition, lower tumorigenic risk, superior immune tolerance, stability compared with stem make an attractive option The therapeutic consequently been evaluated application this review, we summarize mechanisms repair provide evidence to support clinical application. Cardiovascular diseases, particular coronary heart disease (CHD), remain leading cause morbidity mortality worldwide (Virani et al., 2020Virani S.S. Alonso A. Benjamin E.J. Bittencourt M.S. Callaway C.W. Carson A.P. Chamberlain A.M. Chang A.R. Cheng S. Delling F.N. al.Heart stroke statistics—2020 update: report from American Heart Association.Circulation. 2020; 141: e139-e151Crossref PubMed Scopus (2212) Google Scholar). Among all CHDs, acute myocardial infarction (MI) is major death. Consequent complications such as failure contribute significant medical, social, financial burden. A broad spectrum reperfusion strategies available, thrombolytic therapy or primary percutaneous intervention, well anti-remodeling medications angiotensin-converting enzyme drugs β-blockers. Nonetheless there no effective pharmacological intervention prevents cardiomyocyte death due ischemia/reperfusion (I/R) injury (Heusch Gersh, 2017Heusch G. Gersh B.J. pathophysiology protection beyond reperfusion: continual challenge.Eur. J. 2017; 38: 774-784PubMed This I/R may also fibrosis, remodeling, arrhythmia, and, eventually, (Frank 2012Frank Bonney M. Weitzel L. Koeppen Eckle T. Myocardial ischemia injury: basic science bedside.Semin. Cardiothorac. Vasc. Anesth. 2012; 16: 123-132Crossref (256) At end stage, only available transplantation permanent left ventricular (LV) support. There therefore tremendous interest need novel therapies post-MI LV remodeling dysfunction. last few years great advances ultimate aim generate sufficient functional cardiomyocytes compensate those lost following MI, either exogenous by activating endogenous (Menasche, 2018Menasche P. Cell trials regeneration—lessons learned future directions.Nat. Rev. Cardiol. 2018; 15: 659-671Crossref (124) (MSCs) multipotent reside various organs be derived multiple tissues including bone marrow (BM) stroma, adipose tissue, muscle, skin, fallopian umbilical cord blood, menstrual even induced pluripotent (iPSCs) (Caplan, 1991Caplan A.I. cells.J. Orthop. Res. 1991; 9: 641-650Crossref (3273) Scholar; Jackson 2010Jackson W.M. Nesti L.J. Tuan R.S. Potential applications muscle-derived mesenchymal progenitor cells.Expert Opin. Biol. Ther. 2010; 10: 505-517Crossref (87) Lian 2010Lian Q. Zhang Y. H.K. Wu X. Lam F.F. Kang Xia J.C. Lai W.H. al.Functional human attenuate limb mice.Circulation. 121: 1113-1123Crossref (383) strong paracrine MSCs pathways. intravenous, intracoronary, intramyocardial administration improve function MI model (Bagno 2018Bagno Hatzistergos K.E. Balkan W. Hare J.M. cardiovascular disease: progress challenges.Mol. 26: 1610-1623Abstract Full Text PDF (115) Hu 2016Hu Xu Zhong Z. Zhao Wang H. Kong F. Chen al.A large-scale investigation hypoxia-preconditioned allogeneic nonhuman primates: activity without remuscularization.Circ. 2016; 118: 970-983Crossref (110) Liao 2019Liao Ting Zhen Luo Zhu Jiang Sun W.-H. al.Potent immunomodulation angiogenic versus treatment failure.Stem 2019; 78Crossref (22) Moreover, our previous study showed pre-transplantation systemic intravenous improved retention efficacy intramyocardially transplanted (Sun 2021Sun S.-J. Wei R. S.-Y. Tse H.-F. Immunomodulation cell-derived enhance infarction.Theranostics. 2021; 11: 1641-1654Crossref (6) Accumulating shows ameliorate (de Abreu 2020de R.C. Fernandes da Costa Martins P.A. Sahoo Emanueli C. Ferreira Native bioengineered extracellular vesicles therapeutics.Nat. 17: 685-697Crossref (46) discuss describe underlying benefits MSC-exosome-based Additionally, approaches production exosomes. Exosomes diameter 30–150 nm. Previous shown they secreted endosomes, stored multivesicular endosomes (MVEs), released through exocytosis (Doyle Wang, 2019Doyle L.M. M.Z. Overview vesicles, origin, composition, purpose, methods exosome isolation analysis.Cells. 8: 727Crossref destiny release into space fusion MVEs plasma membrane degradation lysosomes along transfers messages target three possible pathways (Figure 1). First, receptors protein microRNA (miRNA) composition transferred recipient fusion. Second, several ligands heat-shock proteins activate cells. Third, miRNAs endocytosis (Loyer 2014Loyer Vion A.-C. Tedgui Boulanger C.M. Microvesicles cell-cell messengers diseases.Circ. 2014; 114: 345-353Crossref (272) one main mediators regulate communication. Barile 2012Barile Gherghiceanu Popescu Moccetti Vassalli Ultrastructural secretion adult mouse myocardium cardiospheres.J. Biomed. Biotechnol. 2012: 354605Crossref (58) Scholar observed were absorbed cardiomyocytes. ultrastructural indicated indeed MSC-cardiomyocyte communication modulated exerted cardioprotective effect partly releasing Administration recently recapitulate advantages using rather than risk tumorigenicity MSC-based (Barkholt 2013Barkholt Flory E. Jekerle V. Lucas-Samuel Ahnert Bisset Buscher D. Fibbe Foussat Kwa al.Risk therapies—bridging scientific observations regulatory viewpoints.Cytotherapy. 2013; 753-759Abstract (202) Scholar), whereas tumor formation exosome-based inflammatory cytokine interferon-γ (IFN-γ) increase expression HLA rejection 2015Sun Y.Q. Li Deng M.X. Gao W.X. Yao Chiu S.M. Liang Chan al.Insensitivity iPS cells-derived interferon-gamma-induced potentiates efficiency hind humanized NOD scid gamma mice.Stem Cells. 2015; 33: 3452-3467Crossref (47) reported more stable store (Lener 2015Lener Gimona Aigner Borger Buzas Camussi Chaput N. Chatterjee Court F.A. Del Portillo H.A. al.Applying based therapeutics trials—an ISEV position paper.J. Extracell. Vesicles. 4: 30087Crossref (652) Fourth, cost Finally, particle size much smaller cells, could travel across capillaries plugging. Therefore, efficacious after administration. summary, mounting demonstrates not beneficial but overcome some limitations (Table 1).Table 1The over cellsMSCMSC-derived exosomesRisk tumorigenicitylownoImmune rejectionlownoStabilitylowhighProduction costhighlowTherapeutic deliverylowhighMSC, cell. Open table new tab MSC, Use still at early ongoing. Table 2 summarizes findings pre-clinical (Arslan 2013Arslan Smeets M.B. Akeroyd Choo Aguor E.N.E. Timmers van Rijen H.V. Doevendans Pasterkamp al.Mesenchymal ATP levels, decrease oxidative stress PI3K/Akt pathway viability prevent adverse injury.Stem 301-312Abstract (676) Bian 2014Bian Duan Min Yu Extracellular promote angiogenesis rat model.J. Mol. Med. 92: 387-397Crossref (420) Feng 2014Feng Huang Wani Ashraf Ischemic preconditioning protective targeting Mecp2 via miR-22.PLoS One. e88685Crossref (287) He 2018He J.-G. H.-R. Han J.-X. B.-B. Yan H.-Y. GATA-4-expressing exosomes.Sci. Rep. 9047Crossref (37) Ju 2018Ju Shen Ma Liu Cai Kim I.-M. Weintraub N.L. Tang Transplantation promotes ischemic myocardium.J. Cardiovasc. Trans. 420-428Crossref 2020Liu Hong Fan B. overexpressing MIF repair.J. Physiol. 235: 8010-8022Crossref (28) Luther 2018Luther K.M. Haar McGuinness Lynch T.L. Phan Song Gardner Kuffel al.Exosomal miR-21a-5p mediates cardioprotection 119: 125-137Abstract (82) Lv 2019Lv K. Lin Xiao al.Incorporation small sodium alginate hydrogel strategy 7403-7416Crossref 2017Ma Qian Akt-modified platelet-derived growth factor D.Stem Cells Transl. 6: 51-59Crossref (163) Scholar, 2018Ma Meng Shao Yang al.MicroRNA-132, delivered exosomes, infarction.Stem Int. 2018: 3290372Crossref (105) Mao 2019Mao X.-L. C.-L. Pang Y.-H. Lu Y.-X. LncRNA KLF3-AS1 ameliorates pyroptosis miR-138-5p/Sirt1 axis.Stem 393Crossref (59) Ni 2019Ni Yin Y.-W. TIMP2-modified possibly Akt/Sfrp2 pathway.Oxid. Longev. 2019: 1958941Crossref (30) 2017Shao Lan Geng Y.-j. X.-y. al.MiRNA-sequence indicates similar mechanism repair.Biomed. 2017: 4150705Crossref (150) 2017Wang Zhou Zeng miR-210, infarcted promotion angiogenesis.Biochim. Biophys. Acta Basis Dis. 1863: 2085-2092Crossref (109) 2018aWang al.Engineered myocardium-targeting peptide targeted infarction.J. Am. Assoc. 7: e008737Crossref (95) 2018Xiao al.Transplanted reduce autophagic flux hearts exosomal transfer miR-125b.Circ. 123: 564-578Crossref (100) 2020Xu marrow, blood Biochem. 2089-2102Crossref (24) 2013Yu Gong Millard Pasha Cardiomyocyte GATA-4 gene engineered partially mediated translocation miR-221 microvesicles.PLoS e73304Crossref (88) 2019Zhao Qiao Xie ischaemia-reperfusion miR-182-regulated macrophage polarization.Cardiovasc. 115: 1205-1216Crossref (174) Scholar) on use Application BM-MSCs (Bian embryonic (ESC)-MSCs (UC)-MSCs (Ma (AD)-MSCs (Xu (Ju resulted significantly MI. these BM-MSC-derived vesicle 30 180 nm most widely used regeneration. Intramyocardial two commonly modes delivery. For mice, 20–50 μg while 1–600 rats, 40–400 20–80 studies, administered immediately induction Other when occurred min, 48 h, 1 week was improved. define issues needed clarified: (1) source cells; (2) distribution; (3) components Here, illustrate underlie enhancing therapy.Table 2Pre-clinical repairNo.AuthorsYearModelCell sourceCell typeSize EVAdministrationTimeDoseEffect1Arslan al.2013myocardial (mouse)humanESC-MSC–intracoronary5 min prior 3 h after0.4 μg/mLreduced size, decreased dilation, increased function, loss2Yu (rat)ratBM-MSCaverage: 100 nmintramyocardialimmediatelyderived 4 × 106 MSCreduced CM apoptosis, function3Bian al.2014MI (rat)humanBM-MSC47–180 nmintramyocardial30 MI80 μgimproved promoted angiogenesis4Feng (mouse)mouseBM-MSCaverage: 57.4 nmintramyocardialimmediately1 μgdecreased apoptosis5Ma al.2017MI (rat)humanUC-MSCaverage: 96 nmintravenousimmediately400 angiogenesis6Shao (rat)ratBM-MSC–intramyocardialimmediately20 reduced inflammation7Wang (mouse)mouseBM-MSC–intravenousimmediately–improved function8He al.2018MI (mouse)mouseBM-MSC–intravenous48 MI20 angiogenesis9Ju (mouse)mouseC-MSCaverage: 120 nmintramyocardialimmediately50 angiogenesis10Luther (mouse)mouseBM-MSC–pericardial sacimmediately12.5 apoptosis11Wang (mouse)mouseBM-MSC30–150 nmintravenousimmediately50 angiogenesis, inflammation12Xiao (mouse)humanBM-MSC–intramyocardial30 MI5 apoptosis13Xu (rat)humanBM-MSC, AD-MSC, UC-MSCBM-MSC: 40–100 nm; AD-MSC: 30–100 UC-MSC: 10–90 MIderived 1.5 MSCimproved apoptosis inflammation14Ma (mouse)mouseBM-MSC<150 nmintramyocardial1 MI600 angiogenesis15Mao al.2019MI (rat)humanMSC30–150 nmintravenousimmediately40 inflammation16Ni (rat)humanUC-MSC40–90 angiogenesis17Lv 90 inflammation, angiogenesis18Zhao al.2019myocardial (mouse)mouseBM-MSC50–150 inflammation19Liu al.2020MI (rat)humanBM-MSCaverage: 50 nmintramyocardialimmediately30 apoptosisMSC, cell; EV, vesicle; infarction; I/R, ischemia/reperfusion; ESC, BM, marrow; UC, cord; AD, adipose; LV, ventricle; ATP, adenosine triphosphate; CM, cardiomyocyte. anti-inflammatory include regulating polarization macr

Language: Английский

Mesenchymal stem cell-derived extracellular vesicles: novel frontiers in regenerative medicine DOI Creative Commons
Somayeh Keshtkar,

Negar Azarpira,

Mohammad Hossein Ghahremani

et al.

Stem Cell Research & Therapy, Journal Year: 2018, Volume and Issue: 9(1)

Published: March 9, 2018

Mesenchymal stem cells (MSCs) are multipotent that have gained significant attention in the field of regenerative medicine. The differentiation potential along with paracrine properties MSCs made them a key option for tissue repair. functions applied through secreting soluble factors and releasing extracellular vesicles like exosomes microvesicles. Extracellular predominantly endosomal origin contain cargo miRNA, mRNA, proteins transferred from their original to target cells. Recently it has emerged alone responsible therapeutic effect plenty animal diseases models. Hence, MSC-derived may be used as an alternative MSC-based therapy In this review we discuss various diseases.

Language: Английский

Citations

721
Mesenchymal stem cell derived-exosomes: a modern approach in translational medicine DOI Creative Commons
Sepideh Nikfarjam, Jafar Rezaie, Naime Majidi Zolbanin

et al.

Journal of Translational Medicine, Journal Year: 2020, Volume and Issue: 18(1)

Published: Nov. 27, 2020

Abstract Mesenchymal stem cells (MSCs) have captured great attention in regenerative medicine for over a few decades by virtue of their differentiation capacity, potent immunomodulatory properties, and ability to be favorably cultured manipulated. Recent investigations implied that the pleiotropic effects MSCs is not associated differentiation, but rather mediated secretion soluble paracrine factors. Exosomes, nanoscale extracellular vesicles, are one these mediators. Exosomes transfer functional cargos like miRNA mRNA molecules, peptides, proteins, cytokines lipids from recipient cells. participate intercellular communication events contribute healing injured or diseased tissues organs. Studies reported exosomes alone responsible therapeutic numerous experimental models. Therefore, MSC-derived can manipulated applied establish novel cell-free approach treatment variety diseases including heart, kidney, liver, immune neurological diseases, cutaneous wound healing. In comparison with donor cells, offer more stable entities diminished safety risks regarding administration live e.g. microvasculature occlusion risk. This review discusses exosome isolation methods invented utilized clinical setting thus far presents summary current information on MSC translational medicine.

Language: Английский

Citations

329
Mesenchymal Stromal/Stem Cells in Regenerative Medicine and Tissue Engineering DOI Creative Commons
Ross Fitzsimmons, Matthew Mazurek, Agnes Soos

et al.

Stem Cells International, Journal Year: 2018, Volume and Issue: 2018, P. 1 - 16

Published: Aug. 19, 2018

As a result of over five decades investigation, mesenchymal stromal/stem cells (MSCs) have emerged as versatile and frequently utilized cell source in the fields regenerative medicine tissue engineering. In this review, we summarize history MSC research from initial discovery their multipotency to more recent recognition perivascular identity vivo extraordinary capacity for immunomodulation angiogenic signaling. well, discuss long-standing questions regarding developmental origins differentiation toward range lineages. We also highlight important considerations potential risks involved with isolation, ex expansion, clinical use. Overall, review aims serve an overview breadth that has demonstrated utility MSCs wide contexts continues unravel mechanisms by which these exert therapeutic effects.

Language: Английский

Citations

322
Biomaterials Functionalized with MSC Secreted Extracellular Vesicles and Soluble Factors for Tissue Regeneration DOI Creative Commons
Meadhbh Á. Brennan, Pierre Layrolle, David Mooney

et al.

Advanced Functional Materials, Journal Year: 2020, Volume and Issue: 30(37)

Published: March 11, 2020

The therapeutic benefits of mesenchymal stromal cell (MSC) transplantation have been attributed to their secreted factors, including extracellular vesicles (EVs) and soluble factors. potential employing the MSC secretome as an alternative acellular approach therapy is being investigated in various tissue injury indications, but EVs administered via bolus injections are rapidly sequestered cleared. However, biomaterials offer delivery platforms enhance EV retention rates healing efficacy. In this review, we highlight mechanisms underpinning effects MSC-EVs factors effectors immunomodulation regeneration, conferred primarily nucleic acid protein contents. We discuss how manipulating culture microenvironment or genetic modification MSCs can further augment potency secretions. most recent advances development EV-functionalized that mediate enhanced angiogenesis survival, while attenuating inflammation fibrosis, presented. Finally, some technical challenges be considered for clinical translation carrying MSC-secreted bioactive cargo discussed.

Language: Английский

Citations

298
Recent Advances in miRNA Delivery Systems DOI Creative Commons
Ishani Dasgupta, Anushila Chatterjee

Methods and Protocols, Journal Year: 2021, Volume and Issue: 4(1), P. 10 - 10

Published: Jan. 20, 2021

MicroRNAs (miRNAs) represent a family of short non-coding regulatory RNA molecules that are produced in tissue and time-specific manner to orchestrate gene expression post-transcription. MiRNAs hybridize target mRNA(s) induce translation repression or mRNA degradation. Functional studies have demonstrated miRNAs engaged virtually every physiological process and, consequently, miRNA dysregulations been linked multiple human pathologies. Thus, mimics anti-miRNAs restore downregulate aberrantly expressed miRNAs, respectively, highly sought-after therapeutic strategies for effective manipulation levels. In this regard, carrier vehicles facilitate proficient safe delivery miRNA-based therapeutics fundamental the clinical success these pharmaceuticals. Here, we highlight strengths weaknesses current state-of-the-art viral non-viral systems provide perspective on how tools can be exploited improve outcomes therapeutics.

Language: Английский

Citations

226
MiRNA-210: A Current Overview DOI Open Access
Alberto Bavelloni, Giulia Ramazzotti, Alessandro Poli

et al.

Anticancer Research, Journal Year: 2017, Volume and Issue: 37(12)

Published: Dec. 3, 2017

microRNAs (miRNAs) are a group of highly conserved small non-coding RNAs that were found to enhance mRNA degradation or inhibit post-transcriptional translation. Accumulating evidence indicates miRNAs contribute tumorigenesis and cancer metastasis. microRNA-210 has been largely studied in the past several years identified as major miRNA induced under hypoxia. A variety miR-210 targets have pointing its role, not only mitochondrial metabolism, but also angiogenesis, DNA damage response, cell proliferation, apoptosis. Based on earlier research findings, this review aims provide current overview involvement miRNA-210 biological processes diseases.

Language: Английский

Citations

206
Cardioprotective microRNAs: Lessons from stem cell-derived exosomal microRNAs to treat cardiovascular disease DOI
Abbas Shapouri Moghaddam, Jalil Tavakol Afshari, Seyed‐Alireza Esmaeili

et al.

Atherosclerosis, Journal Year: 2019, Volume and Issue: 285, P. 1 - 9

Published: March 23, 2019

Language: Английский

Citations

178
Biodistribution of Exosomes and Engineering Strategies for Targeted Delivery of Therapeutic Exosomes DOI Creative Commons
Hojun Choi, Yoorim Choi, Hwa Young Yim

et al.

Tissue Engineering and Regenerative Medicine, Journal Year: 2021, Volume and Issue: 18(4), P. 499 - 511

Published: July 14, 2021

Abstract Exosomes are cell-secreted nano-sized vesicles which deliver diverse biological molecules for intercellular communication. Due to their therapeutic potential, exosomes have been engineered in numerous ways efficient delivery of active pharmaceutical ingredients various target organs, tissues, and cells. In vivo administered normally delivered the liver, spleen, kidney, lung, gastrointestinal tract show rapid clearance from blood circulation after systemic injection. The biodistribution pharmacokinetics (PK) can be modulated by engineering factors such as cellular origin membrane protein composition exosomes. Recent advances accentuate potential targeted even most challenging organs including central nervous system. Major breakthroughs made related imaging techniques monitoring PK exosomes, well exosomal surface technologies inducing targetability. For delivery, express targeting moieties via direct modification methods chemically modifying surfaces with covalent/non-covalent bonds, or indirect genetically exosome-producing this review, we describe current knowledge determining targetability organotropism monitor addition, highlight recent strategies specific

Language: Английский

Citations

163
Extracellular vesicles for tissue repair and regeneration: Evidence, challenges and opportunities DOI
Anika Nagelkerke, Miina Ojansivu, Luke van der Koog

et al.

Advanced Drug Delivery Reviews, Journal Year: 2021, Volume and Issue: 175, P. 113775 - 113775

Published: April 17, 2021

Language: Английский

Citations

135
Mesenchymal stem/stromal cell-derived exosomes in regenerative medicine and cancer; overview of development, challenges, and opportunities DOI Creative Commons
Ali Hassanzadeh, Heshu Sulaiman Rahman, Alexander Markov

et al.

Stem Cell Research & Therapy, Journal Year: 2021, Volume and Issue: 12(1)

Published: May 21, 2021

Abstract Recently, mesenchymal stem/stromal cells (MSCs) and their widespread biomedical applications have attracted great consideration from the scientific community around world. However, reports shown that main populations of transplanted MSCs are trapped in liver, spleen, lung upon administration, highlighting importance development cell-free therapies. Concerning rising evidence suggesting beneficial effects MSC therapy closely linked to MSC-released components, predominantly MSC-derived exosomes, an MSC-based approach is paramount importance. The exosomes nano-sized (30–100 nm) lipid bilayer membrane vesicles, which typically released by found different body fluids. They include various bioactive molecules, such as messenger RNA (mRNA), microRNAs, proteins, lipids, thus showing pronounced therapeutic competence for tissues recovery through maintenance endogenous stem cells, enhancement regenerative phenotypic traits, inhibition apoptosis concomitant with immune modulation, stimulation angiogenesis. Conversely, specific roles treatment tumors remain challenging. clinical application novel strategies can be supported better understanding mechanisms, classifying subpopulation enhancing conditions cell culture isolation, increasing production along engineering deliver drugs molecules target sites. In current review, we a brief overview exosome biogenesis, composition, isolation methods discuss recent investigation regarding potential medicine accompanied double-edged sword role cancer.

Language: Английский

Citations

126