Acute myocardial infarction (AMI) is an event of ischemic myocardial necrosis caused by acute coronary artery occlusion, which ultimately leads to a large loss of cardiomyocytes. The prerequisite of salvaging ischemic myocardium and improving cardiac function of patients is to provide adequate blood perfusion in the infarcted area. Apart from reperfusion therapy, it is also urgent and imperative to promote angiogenesis. Recently, growing evidence based on promising preclinical data indicates that mesenchymal stem cells (MSCs) can provide therapeutic effects on AMI by promoting angiogenesis. Extracellular vesicles (EVs), membrane-encapsulated vesicles with complex cargoes, including proteins, nucleic acids, and lipids, can be derived from MSCs and represent part of their functions, so EVs also possess the ability to promote angiogenesis. However, poor control of the survival and localization of MSCs hindered clinical transformation and made scientists start looking for new approaches based on MSCs. Identifying the role of MSCs and their derived EVs in promoting angiogenesis can provide a theoretical basis for improved MSC-based methods, and ultimately promote the clinical treatment of AMI. This review highlights potential proangiogenic mechanisms of transplanted MSCs and the derived EVs after AMI and summarizes the latest literature concerning the novel methods based on MSCs to maximize the angiogenesis capability.
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References
1.
NiccoliG, BurzottaF, GaliutoL and CreaF. (2009). Myocardial no-reflow in humans. J Am Coll Cardiol, 54:281–292.
2.
(2013). Angiogenesis in the infarcted myocardium. Antioxid Redox Signal, 18:1100–1113.
3.
HuangC, GuH, YuQ, ManukyanMC, PoynterJA and WangM. (2011). Sca-1+ cardiac stem cells mediate acute cardioprotection via paracrine factor SDF-1 following myocardial ischemia/reperfusion. PLoS One, 6:e29246.
4.
SongG, LiX, ShenY, QianL, KongX, ChenM, CaoK and ZhangF. (2015). Transplantation of iPSc restores cardiac function by promoting angiogenesis and ameliorating cardiac remodeling in a post-infarcted swine model. Cell Biochem Biophys, 71:1463–1473.
5.
WuQ, WangJ, TanWLW, JiangY, WangS, LiQ, YuX, TanJ, LiuS, et al. (2020). Extracellular vesicles from human embryonic stem cell-derived cardiovascular progenitor cells promote cardiac infarct healing through reducing cardiomyocyte death and promoting angiogenesis. Cell Death Dis, 11:354.
6.
DonghaiG, QiangliW, XiaojingH, ZhirongL and LishengZ. (2017). Clinical study on computerized molecular imaging tracing stem cell transplantation for patients with myocardial infarction. Proced Eng, 174:1380–1386.
7.
PittengerMF, MackayAM, BeckSC, JaiswalRK, DouglasR, MoscaJD, MoormanMA, SimonettiDW, CraigS and MarshakDR. (1999). Multilineage potential of adult human mesenchymal stem cells. Science, 284:143–147.
KhatriR, PetrySF and LinnT. (2021). Intrapancreatic MSC transplantation facilitates pancreatic islet regeneration. Stem Cell Res Ther, 12:121.
10.
KimSH, ChoJH, LeeYH, LeeJH, KimSS, KimMY, LeeMG, KangWY, LeeKS, et al. (2018). Improvement in left ventricular function with intracoronary mesenchymal stem cell therapy in a patient with anterior wall ST-segment elevation myocardial infarction. Cardiovasc Drugs Ther, 32:329–338.
11.
BartolucciJ, VerdugoFJ, GonzálezPL, LarreaRE, AbarzuaE, GosetC, RojoP, PalmaI, LamichR, et al. (2017). Safety and efficacy of the intravenous infusion of umbilical cord mesenchymal stem cells in patients with heart failure: a phase 1/2 randomized controlled trial (RIMECARD Trial [Randomized Clinical Trial of Intravenous Infusion Umbilical Cord Mesenchymal Stem Cells on Cardiopathy]). Circ Res, 121:1192–1204.
12.
LaluMM, MazzarelloS, ZlepnigJ, DongYYR, MontroyJ, McIntyreL, DevereauxPJ, StewartDJ, David MazerC, et al. (2018). Safety and efficacy of adult stem cell therapy for acute myocardial infarction and ischemic heart failure (safecell heart): a systematic review and meta-analysis. Stem Cells Transl Med, 7:857–866.
13.
TangJ, XieQ, PanG, WangJ and WangM. (2006). Mesenchymal stem cells participate in angiogenesis and improve heart function in rat model of myocardial ischemia with reperfusion. Eur J Cardiothorac Surg, 30:353–361.
14.
GongM, YuB, WangJ, WangY, LiuM, PaulC, MillardRW, XiaoDS, AshrafM and XuM. (2017). Mesenchymal stem cells release exosomes that transfer miRNAs to endothelial cells and promote angiogenesis. Oncotarget, 8:45200–45212.
15.
KaoCY and PapoutsakisET. (2019). Extracellular vesicles: exosomes, microparticles, their parts, and their targets to enable their biomanufacturing and clinical applications. Curr Opin Biotechnol, 60:89–98.
16.
BianS, ZhangL, DuanL, WangX, MinY and YuH. (2014). Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model. J Mol Med (Berl), 92:387–397.
17.
NygrenJM, JovingeS, BreitbachM, SäwénP, RöllW, HeschelerJ, TaneeraJ, FleischmannBK and JacobsenSE. (2004). Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nat Med, 10:494–501.
18.
Otto BeitnesJ, OieE, ShahdadfarA, KarlsenT, MüllerRM, AakhusS, ReinholtFP and BrinchmannJE. (2012). Intramyocardial injections of human mesenchymal stem cells following acute myocardial infarction modulate scar formation and improve left ventricular function. Cell Transplant, 21:1697–1709.
19.
VaderP, BreakefieldXO and WoodMJA. (2014). Extracellular vesicles: emerging targets for cancer therapy. Trends Mol Med, 20:385–393.
20.
KwonHM, HurSM, ParkKY, KimCK, KimYM, KimHS, ShinHC, WonMH, HaKS, et al. (2014). Multiple paracrine factors secreted by mesenchymal stem cells contribute to angiogenesis. Vascul Pharmacol, 63:19–28.
21.
BoomsmaRA and GeenenDL. (2012). Mesenchymal stem cells secrete multiple cytokines that promote angiogenesis and have contrasting effects on chemotaxis and apoptosis. PLoS One, 7:e35685.
22.
TangYL, ZhaoQ, QinX, ShenL, ChengL, GeJ and PhillipsMI. (2005). Paracrine action enhances the effects of autologous mesenchymal stem cell transplantation on vascular regeneration in rat model of myocardial infarction. Ann Thorac Surg, 80:229–236; discussion 236–237.
23.
YaoY, HuangJ, GengY, QianH, WangF, LiuX, ShangM, NieS, LiuN, et al. (2015). Paracrine action of mesenchymal stem cells revealed by single cell gene profiling in infarcted murine hearts. PLoS One, 10:e0129164.
24.
GerberHP, McMurtreyA, KowalskiJ, YanM, KeytBA, DixitV and FerraraN. (1998). Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3'-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem, 273:30336–30343.
25.
MeadowsKN, BryantP and PumigliaK. (2001). Vascular endothelial growth factor induction of the angiogenic phenotype requires Ras activation. J Biol Chem, 276:49289–49298.
26.
ZouJ, FeiQ, XiaoH, WangH, LiuK, LiuM, ZhangH, XiaoX, WangK and WangN. (2019). VEGF-A promotes angiogenesis after acute myocardial infarction through increasing ROS production and enhancing ER stress-mediated autophagy. J Cell Physiol, 234:17690–17703.
27.
TangYL, ZhaoQ, ZhangYC, ChengLL, LiuMY, ShiJH, YangYZ, PanCZ, GeJB and PhillipsMI. (2004). Autologous mesenchymal stem cell transplantation induce VEGF and neovascularization in ischemic myocardium. Regul Pept, 117:3–10.
28.
AnY, LiuWJ, XueP, MaY, ZhangLQ, ZhuB, QiM, LiLY, ZhangYJ, WangQT and JinY. (2018). Autophagy promotes MSC-mediated vascularization in cutaneous wound healing via regulation of VEGF secretion. Cell Death Dis, 9:58.
29.
ZhangJ, WuY, ChenA and ZhaoQ. (2015). Mesenchymal stem cells promote cardiac muscle repair via enhanced neovascularization. Cell Physiol Biochem, 35:1219–1229.
30.
OkuyamaH, KrishnamacharyB, ZhouYF, NagasawaH, Bosch-MarceM and SemenzaGL. (2006). Expression of vascular endothelial growth factor receptor 1 in bone marrow-derived mesenchymal cells is dependent on hypoxia-inducible factor 1. J Biol Chem, 281:15554–15563.
31.
ZhangJF, ChenAQ, WuYC and ZhaoQ. (2015). Placental growth factor promotes cardiac muscle repair via enhanced neovascularization. Cell Physiol Biochem, 36:947–955.
32.
TchaikovskiV, FellbrichG and WaltenbergerJ. (2008). The molecular basis of VEGFR-1 signal transduction pathways in primary human monocytes. Arterioscler Thromb Vasc Biol, 28:322–328.
33.
KinnairdT, StabileE, BurnettMS, ShouM, LeeCW, BarrS, FuchsS and EpsteinSE. (2004). Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation, 109:1543–1549.
34.
UngerEF, BanaiS, ShouM, LazarousDF, JaklitschMT, ScheinowitzM, CorreaR, KlingbeilC and EpsteinSE. (1994). Basic fibroblast growth factor enhances myocardial collateral flow in a canine model. Am J Physiol, 266:H1588–H1595.
35.
HughesGC, BiswasSS, YinB, ColemanRE, DeGradoTR, LandolfoCK, LoweJE, AnnexBH and LandolfoKP. (2004). Therapeutic angiogenesis in chronically ischemic porcine myocardium: comparative effects of bFGF and VEGF. Ann Thorac Surg, 77:812–818.
36.
LiuY, SunL, HuanY, ZhaoH and DengJ. (2006). Effects of basic fibroblast growth factor microspheres on angiogenesis in ischemic myocardium and cardiac function: analysis with dobutamine cardiovascular magnetic resonance tagging. Eur J Cardiothorac Surg, 30:103–107.
37.
BougioukasI, DidilisV, YpsilantisP, GiatromanolakiA, SivridisE, LialiarisT, MikroulisD, SimopoulosC and BougioukasG. (2007). Intramyocardial injection of low-dose basic fibroblast growth factor or vascular endothelial growth factor induces angiogenesis in the infarcted rabbit myocardium. Cardiovasc Pathol, 16:63–68.
38.
Shi Y-h, Y-x Wang, BingleL, L-h Gong, W-j Heng, LiY and FangW-g. (2005). In vitro study of HIF-1 activation and VEGF release by bFGF in the T47D breast cancer cell line under normoxic conditions: involvement of PI-3K/Akt and MEK1/ERK pathways. J Pathol, 205:530–536.
39.
ShiY-H, BingleL, GongL-H, WangY-X, CorkeKP and FangW-G. (2007). Basic FGF augments hypoxia induced HIF-1-alpha expression and VEGF release in T47D breast cancer cells. Pathology, 39:396–400.
40.
NakamuraY, MorishitaR, HigakiJ, KidaI, AokiM, MoriguchiA, YamadaK, HayashiS, YoY, et al. (1996). Hepatocyte growth factor is a novel member of the endothelium-specific growth factors: additive stimulatory effect of hepatocyte growth factor with basic fibroblast growth factor but not with vascular endothelial growth factor. J Hypertension, 14:1067–1072.
41.
SenguptaS, GherardiE, SellersLA, WoodJM, SasisekharanR and FanTPD. (2003). Hepatocyte growth factor/scatter factor can induce angiogenesis independently of vascular endothelial growth factor. Arterioscler Thromb Vasc Biol, 23:69–75.
42.
LuF, ZhaoX, WuJ, CuiY, MaoY, ChenK, YuanY, GongD, XuZ and HuangS. (2013). MSCs transfected with hepatocyte growth factor or vascular endothelial growth factor improve cardiac function in the infarcted porcine heart by increasing angiogenesis and reducing fibrosis. Int J Cardiol, 167:2524–2532.
43.
YangY, ChenQH, LiuAR, XuXP, HanJB and QiuHB. (2015). Synergism of MSC-secreted HGF and VEGF in stabilising endothelial barrier function upon lipopolysaccharide stimulation via the Rac1 pathway. Stem Cell Res Ther, 6:14.
44.
LinSY, ZhangQ, ShaoXR, ZhangT, XueCY, ShiSR, ZhaoD and LinYF. (2017). IGF-1 promotes angiogenesis in endothelial cells/adipose-derived stem cells co-culture system with activation of PI3K/Akt signal pathway. Cell Proliferation, 50:10.
45.
TasarO, KocabayG, KarabagY, KarabayAK, KarabayCY, KalkanS and KirmaC. (2020). Insulin-like growth factor-1 levels predict myocardial injury and infarction after elective percutaneous coronary intervention: an optical coherence tomography study. Postepy Kardiol Interwencyjnej, 16:162–169.
46.
HsiaoST, AsgariA, LokmicZ, SinclairR, DustingGJ, LimSY and DilleyRJ. (2012). Comparative analysis of paracrine factor expression in human adult mesenchymal stem cells derived from bone marrow, adipose, and dermal tissue. Stem Cells Dev, 21:2189–2203.
47.
HuangY, KuangJ, HuY, SongY, QiuR and MaiW. (2012). Bone marrow stromal cell transplantation combined with angiotensin-converting enzyme inhibitor treatment in rat with acute myocardial infarction and the role of insulin-like growth factor-1. Cytotherapy, 14:563–569.
48.
AngoulvantD, IvanesF, FerreraR, MatthewsPG, NatafS and OvizeM. (2011). Mesenchymal stem cell conditioned media attenuates in vitro and ex vivo myocardial reperfusion injury. J Heart Lung Transplant, 30:95–102.
MorimotoH, TakahashiM, IzawaA, IseH, HongoM, KolattukudyPE and IkedaU. (2006). Cardiac overexpression of monocyte chemoattractant protein-1 in transgenic mice prevents cardiac dysfunction and remodeling after myocardial infarction. Circ Res, 99:891–899.
51.
MaJ, WangQ, FeiT, HanJDJ and ChenYG. (2007). MCP-1 mediates TGF-beta-induced angiogenesis by stimulating vascular smooth muscle cell migration. Blood, 109:987–994.
52.
HungSC, PochampallyRR, ChenSC, HsuSC and ProckopDJ. (2007). Angiogenic effects of human multipotent stromal cell conditioned medium activate the PI3K-Akt pathway in hypoxic endothelial cells to inhibit apoptosis, increase survival, and stimulate angiogenesis. Stem Cells, 25:2363–2370.
53.
NiuJ, AzferA, ZhelyabovskaO, FatmaS and KolattukudyPE. (2008). Monocyte chemotactic protein (MCP)-1 promotes angiogenesis via a novel transcription factor, MCP-1-induced protein (MCPIP). J Biol Chem, 283:14542–14551.
54.
NiuJ, JinZ, KimH and KolattukudyP. (2015). MCP-1-induced protein attenuates post-infarct cardiac remodeling and dysfunction through mitigating NF-κB activation and suppressing inflammation-associated microRNA expression. Basic Res Cardiol, 110:483.
55.
Lo CiceroA, StahlP and RaposoG. (2015). Extracellular vesicles shuffling intercellular messages: for good or for bad. Curr opin cell biol, 35:69–77.
ZhangH, XiangM, MengD, SunN and ChenS. (2016). Inhibition of myocardial ischemia/reperfusion injury by exosomes secreted from mesenchymal stem cells. Stem Cells Int, 2016:4328362.
58.
LiuL, JinX, HuCF, LiR, ZhouZ and ShenCX. (2017). Exosomes derived from mesenchymal stem cells rescue myocardial ischaemia/reperfusion injury by inducing cardiomyocyte autophagy via AMPK and Akt pathways. Cell Physiol Biochem, 43:52–68.
59.
PengY, ZhaoJL, PengZY, XuWF and YuGL. (2020). Exosomal miR-25-3p from mesenchymal stem cells alleviates myocardial infarction by targeting pro-apoptotic proteins and EZH2. Cell Death Dis, 11:317.
60.
HuangL, YangL, DingY, JiangX, XiaZ and YouZ. (2020). Human umbilical cord mesenchymal stem cells-derived exosomes transfers microRNA-19a to protect cardiomyocytes from acute myocardial infarction by targeting SOX6. Cell Cycle, 19:339–353.
61.
CervioE, BarileL, MoccettiT and VassalliG. (2015). Exosomes for intramyocardial intercellular communication. Stem Cells Int, 2015:482171.
62.
BridgeG, MonteiroR, HendersonS, EmussV, LagosD, GeorgopoulouD, PatientR and BoshoffC. (2012). The microRNA-30 family targets DLL4 to modulate endothelial cell behavior during angiogenesis. Blood, 120:5063–5072.
63.
JiangQ, Lagos-QuintanaM, LiuD, ShiY, HelkerC, HerzogW and le NobleF. (2013). miR-30a regulates endothelial tip cell formation and arteriolar branching. Hypertension, 62:592–598.
LiuLZ, LiC, ChenQ, JingY, CarpenterR, JiangY, KungHF, LaiL and JiangBH. (2011). MiR-21 induced angiogenesis through AKT and ERK activation and HIF-1α expression. PLoS One, 6:e19139.
66.
FasanaroP, D'AlessandraY, Di StefanoV, MelchionnaR, RomaniS, PompilioG, CapogrossiMC and MartelliF. (2008). MicroRNA-210 modulates endothelial cell response to hypoxia and inhibits the receptor tyrosine kinase ligand Ephrin-A3. J Biol Chem, 283:15878–15883.
67.
WangN, ChenC, YangD, LiaoQ, LuoH, WangX, ZhouF, YangX, YangJ, ZengC and WangWE. (2017). Mesenchymal stem cells-derived extracellular vesicles, via miR-210, improve infarcted cardiac function by promotion of angiogenesis. Biochim Biophys Acta Mol Basis Dis, 1863:2085–2092.
68.
ChengH, ChangS, XuR, ChenL, SongX, WuJ, QianJ, ZouY and MaJ. (2020). Hypoxia-challenged MSC-derived exosomes deliver miR-210 to attenuate post-infarction cardiac apoptosis. Stem Cell Res Ther, 11:224.
69.
WangS, AuroraAB, JohnsonBA, QiX, McAnallyJ, HillJA, RichardsonJA, Bassel-DubyR and OlsonEN. (2008). The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev Cell, 15:261–271.
70.
WeiYZ, WuYF, ZhaoRX, ZhangKY, MidgleyAC, KongDL, LiZJ and ZhaoQ. (2019). MSC-derived sEVs enhance patency and inhibit calcification of synthetic vascular grafts by immunomodulation in a rat model of hyperlipidemia. Biomaterials, 204:13–24.
71.
YangHH, ChenY, GaoCY, CuiZT and YaoJM. (2017). Protective effects of MicroRNA-126 on human cardiac microvascular endothelial cells against hypoxia/reoxygenation-induced injury and inflammatory response by activating PI3K/Akt/eNOS signaling pathway. Cell Physiol Biochem, 42:506–518.
72.
BottA, ErdemN, LerrerS, Hotz-WagenblattA, BreunigC, AbnaofK, WörnerA, WilhelmH, MünstermannE, Ben-BaruchA and WiemannS. (2017). miRNA-1246 induces pro-inflammatory responses in mesenchymal stem/stromal cells by regulating PKA and PP2A. Oncotarget, 8:43897–43914.
73.
FergusonSW, WangJ, LeeCJ, LiuM, NeelameghamS, CantyJM and NguyenJ. (2018). The microRNA regulatory landscape of MSC-derived exosomes: a systems view. Sci Reports, 8:1419.
74.
AndersonJD, JohanssonHJ, GrahamCS, VesterlundM, PhamMT, BramlettCS, MontgomeryEN, MellemaMS, BardiniRL, et al. (2016). Comprehensive proteomic analysis of mesenchymal stem cell exosomes reveals modulation of angiogenesis via nuclear factor-KappaB signaling. Stem Cells, 34:601–613.
75.
NakamuraY, MiyakiS, IshitobiH, MatsuyamaS, NakasaT, KameiN, AkimotoT, HigashiY and OchiM. (2015). Mesenchymal-stem-cell-derived exosomes accelerate skeletal muscle regeneration. FEBS Lett, 589:1257–1265.
76.
MaoQ, LiangXL, ZhangCL, PangYH and LuYX. (2019). LncRNA KLF3-AS1 in human mesenchymal stem cell-derived exosomes ameliorates pyroptosis of cardiomyocytes and myocardial infarction through miR-138-5p/Sirt1 axis. Stem Cell Res Ther, 10:393.
77.
GongLC, XuHM, GuoGL, ZhangT, ShiJW and ChangC. (2017). Long Non-Coding RNA H19 Protects H9c2 Cells against Hypoxia-Induced Injury by Targeting MicroRNA-139. Cell Physiol Biochem, 44:857–869.
78.
BaglioSR, RooijersK, Koppers-LalicD, VerweijFJ, Pérez LanzónM, ZiniN, NaaijkensB, PerutF, NiessenHW, BaldiniN and PegtelDM. (2015). Human bone marrow- and adipose-mesenchymal stem cells secrete exosomes enriched in distinctive miRNA and tRNA species. Stem Cell Res Ther, 6:127.
79.
TanSS, YinY, LeeT, LaiRC, YeoRW, ZhangB, ChooA and LimSK. (2013). Therapeutic MSC exosomes are derived from lipid raft microdomains in the plasma membrane. J Extracell Vesicles, 2013;2:22614.
80.
TrajkovicK, HsuC, ChiantiaS, RajendranL, WenzelD, WielandF, SchwilleP, BrüggerB and SimonsM. (2008). Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science, 319:1244–1247.
81.
LeeMJ, Van BrocklynJR, ThangadaS, LiuCH, HandAR, MenzeleevR, SpiegelS and HlaT. (1998). Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1. Science, 279:1552–1555.
82.
LeeOH, KimYM, LeeYM, MoonEJ, LeeDJ, KimJH, KimKW and KwonYG. (1999). Sphingosine 1-phosphate induces angiogenesis: its angiogenic action and signaling mechanism in human umbilical vein endothelial cells. Biochem Biophys Res Commun, 264:743–750.
83.
CarusoS and PoonIKH. (2018). Apoptotic Cell-Derived Extracellular Vesicles: More Than Just Debris. Front Immunol, 9:1486.
84.
GolponHA, FadokVA, Taraseviciene-StewartL, ScerbaviciusR, SauerC, WelteT, HensonPM and VoelkelNF. (2004). Life after corpse engulfment: phagocytosis of apoptotic cells leads to VEGF secretion and cell growth. FASEB J, 18:1716–1718.
85.
FriesDM, LightfootR, KovalM and IschiropoulosH. (2005). Autologous apoptotic cell engulfment stimulates chemokine secretion by vascular smooth muscle cells. Am J Pathol, 167:345–353.
86.
LiuH, LiuS, QiuX, YangX, BaoL, PuF, LiuX, LiC, XuanK, et al. (2020). Donor MSCs release apoptotic bodies to improve myocardial infarction via autophagy regulation in recipient cells. Autophagy, 16:2140–2155.
87.
LeeRH, PulinAA, SeoMJ, KotaDJ, YlostaloJ, LarsonBL, Semprun-PrietoL, DelafontaineP and ProckopDJ. (2009). Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell, 5:54–63.
88.
EggenhoferE, BenselerV, KroemerA, PoppFC, GeisslerEK, SchlittHJ, BaanCC, DahlkeMH and HoogduijnMJ. (2012). Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion. Front Immunol, 3:297.
89.
Ju XaD Xue, WangT, GeB, ZhangY and LiZ. (2018). Catalpol promotes the survival and VEGF secretion of bone marrow-derived stem cells and their role in myocardial repair after myocardial infarction in rats. Cardiovasc Toxicol, 18:471–481.
90.
GongXH, FanGP, WangW and WangGG. (2014). Trimetazidine protects umbilical cord mesenchymal stem cells against hypoxia and serum deprivation induced apoptosis by activation of akt. Cell Physiol Biochem, 34:2245–2255.
91.
NumasawaY, KimuraT, MiyoshiS, NishiyamaN, HidaN, TsujiH, TsurutaH, SegawaK, OgawaS and UmezawaA. (2011). Treatment of human mesenchymal stem cells with angiotensin receptor blocker improved efficiency of cardiomyogenic transdifferentiation and improved cardiac function via angiogenesis. Stem Cells, 29:1405–1414.
92.
HuangP, WangL, LiQ, TianX, XuJ, XuJ, XiongY, ChenG, QianH, et al. (2020). Atorvastatin enhances the therapeutic efficacy of mesenchymal stem cells-derived exosomes in acute myocardial infarction via up-regulating long non-coding RNA H19. Cardiovasc Res, 116:353–367.
93.
CostaV, RaimondiL, ConigliaroA, SalamannaF, CarinaV, De LucaA, BellaviaD, AlessandroR, FiniM and GiavaresiG. (2017). Hypoxia-inducible factor 1Α may regulate the commitment of mesenchymal stromal cells toward angio-osteogenesis by mirna-675-5P. Cytotherapy, 19:1412–1425.
94.
LiN, YangYJ, QianHY, LiQ, ZhangQ, LiXD, DongQT, XuH, SongL and ZhangH. (2015). Intravenous administration of atorvastatin-pretreated mesenchymal stem cells improves cardiac performance after acute myocardial infarction: role of CXCR4. Am J Transl Res, 7:1058–1070.
95.
LiuC, FanY, ZhouL, ZhuH-Y, SongY-C, HuL, WangY and LiQ-P. (2015). Pretreatment of mesenchymal stem cells with angiotensin II enhances paracrine effects, angiogenesis, gap junction formation and therapeutic efficacy for myocardial infarction. Int J Cardiol, 188:22–32.
96.
LuoY, WangY, PoynterJA, ManukyanMC, HerrmannJL, AbarbanellAM, WeilBR and MeldrumDR. (2012). Pretreating mesenchymal stem cells with interleukin-1β and transforming growth factor-β synergistically increases vascular endothelial growth factor production and improves mesenchymal stem cell–mediated myocardial protection after acute ischemia. Surgery, 151:353–363.
97.
ChenM-S, LinC-Y, ChiuY-H, ChenC-P, TsaiP-J and WangH-S. (2018). IL-1β-induced matrix metalloprotease-1 promotes mesenchymal stem cell migration via PAR1 and G-protein-coupled signaling pathway. Stem Cells Int, 2018:3524759.
98.
ZhangZ, TanY, ZhuL, ZhangB, FengP, GaoE, XuC, WangX, YiW and SunY. (2019). Asprosin improves the survival of mesenchymal stromal cells in myocardial infarction by inhibiting apoptosis via the activated ERK1/2-SOD2 pathway. Life Sci, 231:116554.
99.
MaQ, XiaX, TaoQ, LuK, ShenJ, XuQ, HuX, TangY, BlockNL, et al. (2016). Profound actions of an agonist of growth hormone-releasing hormone on angiogenic therapy by mesenchymal stem cells. Arterioscler Thromb Vasc Biol, 36:663–672.
100.
WangR, LiuW, DuM, YangC, LiX and YangP. (2018). The differential effect of basic fibroblast growth factor and stromal cell-derived factor-1 pretreatment on bone morrow mesenchymal stem cells osteogenic differentiation potency. Mol Med Rep, 17:3715–3721.
101.
XuJY, QianHY, HuangPS, XuJ, XiongYY, JiangWY, XuY, LengWX, LiXD, et al. (2019). Transplantation efficacy of autologous bone marrow mesenchymal stem cells combined with atorvastatin for acute myocardial infarction (TEAM-AMI): rationale and design of a randomized, double-blind, placebo-controlled, multi-center, Phase II TEAM-AMI trial. Regen med, 14:1077–1087.
102.
LimSY, ChoDI, JeongH-Y, KangH-J, KimMR, ChoM, KimYS and AhnY. (2018). Adjuvant role of macrophages in stem cell-induced cardiac repair in rats. Exp mol med, 50:1–10.
103.
ChoD-I, KimMR, H-y Jeong, JeongHC, JeongMH, YoonSH, KimYS and AhnY. (2014). Mesenchymal stem cells reciprocally regulate the M1/M2 balance in mouse bone marrow-derived macrophages. Exp Mol Med, 46:e70.
104.
LiQ and WangZ. (2013). Influence of mesenchymal stem cells with endothelial progenitor cells in co-culture on osteogenesis and angiogenesis: an in vitro study. Arch Med Res, 44:504–513.
105.
AguirreA, PlanellJA and EngelE. (2010). Dynamics of bone marrow-derived endothelial progenitor cell/mesenchymal stem cell interaction in co-culture and its implications in angiogenesis. Biochem Biophys Res Commun, 400:284–291.
106.
KimS-W, JinHL, KangS-M, KimS, YooK-J, JangY, KimHO and YoonY-s. (2016). Therapeutic effects of late outgrowth endothelial progenitor cells or mesenchymal stem cells derived from human umbilical cord blood on infarct repair. Int J Cardiol, 203:498–507.
107.
SunK, ZhouZ, JuX, ZhouY, LanJ, ChenD, ChenH, LiuM and PangL. (2016). Combined transplantation of mesenchymal stem cells and endothelial progenitor cells for tissue engineering: a systematic review and meta-analysis. Stem Cell Res Ther, 7:151.
108.
WageggM, GaberT, LohanathaFL, HahneM, StrehlC, FangradtM, TranCL, SchönbeckK, HoffP, et al. (2012). Hypoxia promotes osteogenesis but suppresses adipogenesis of human mesenchymal stromal cells in a hypoxia-inducible factor-1 dependent manner. PloS one, 7:e46483.
109.
ZhangZ, YangC, ShenM, YangM, JinZ, DingL, JiangW, YangJ, ChenH, CaoF and HuT. (2017). Autophagy mediates the beneficial effect of hypoxic preconditioning on bone marrow mesenchymal stem cells for the therapy of myocardial infarction. Stem Cell Res Ther, 8:89.
110.
BaderAM, KloseK, BiebackK, KorinthD, SchneiderM, SeifertM, ChoiYH, KurtzA, FalkV and StammC. (2015). Hypoxic preconditioning increases survival and pro-angiogenic capacity of human cord blood mesenchymal stromal cells in vitro. PLoS One, 10:e0138477.
111.
HanKH, KimAK, KimMH, KimDH, GoHN, KangD, ChangJW, ChoiSW, KangKS and KimDI. (2017). Protein profiling and angiogenic effect of hypoxia-cultured human umbilical cord blood-derived mesenchymal stem cells in hindlimb ischemia. Tissue Cell, 49:680–690.
112.
HaoD, HeC, MaB, LankfordL, ReynagaL, FarmerDL, GuoF and WangA. (2019). Hypoxic preconditioning enhances survival and proangiogenic capacity of human first trimester chorionic villus-derived mesenchymal stem cells for fetal tissue engineering. Stem Cells Int, 2019:9695239.
113.
HanY, RenJ, BaiY, PeiX and HanY. (2019). Exosomes from hypoxia-treated human adipose-derived mesenchymal stem cells enhance angiogenesis through VEGF/VEGF-R. Int J Biochem Cell Biol, 109:59–68.
114.
ZhuJ, LuK, ZhangN, ZhaoY, MaQ, ShenJ, LinY, XiangP, TangY, et al. (2018). Myocardial reparative functions of exosomes from mesenchymal stem cells are enhanced by hypoxia treatment of the cells via transferring microRNA-210 in an nSMase2-dependent way. Artif Cells Nanomed Biotechnol, 46:1659–1670.
115.
ParkH, ParkH, MunD, KangJ, KimH, KimM, CuiS, LeeSH and JoungB. (2018). Extracellular Vesicles Derived from Hypoxic Human Mesenchymal Stem Cells Attenuate GSK3β Expression via miRNA-26a in an Ischemia-Reperfusion Injury Model. Yonsei Med J, 59:736–745.
116.
Al-SaqiSH, SaliemM, AsikainenS, QuezadaHC, EkbladA, HovattaO, Le BlancK, JonassonAF and GötherströmC. (2014). Defined serum-free media for in vitro expansion of adipose-derived mesenchymal stem cells. Cytotherapy, 16:915–926.
117.
OskowitzAZ, McferrinHE, GutschowM, CarterML and PochampallyR. (2011). Serum-deprived human multipotent mesenchymal stromal cells (MSCs) are highly angiogenic. Stem Cell Res, 6:215–225.
118.
SellaS, AdamiV, AmatiE, BernardiM, ChieregatoK, GattoP, MenarinM, PozzatoA, PozzatoG and AstoriG. (2018). In-vitro analysis of Quantum Molecular Resonance effects on human mesenchymal stromal cells. PLoS One, 13:e0190082.
119.
De MatteiM, GrassilliS, PellatiA, BrugnoliF, De MarchiE, ContarteseD and BertagnoloV. (2020). Pulsed electromagnetic fields modulate miRNAs during osteogenic differentiation of bone mesenchymal stem cells: a possible role in the osteogenic-angiogenic coupling. Stem Cell Rev Rep, 16:1005–1012.
120.
PrůchaJ, SkopalikJ, JustanI, ParákT, GabrielováE, HánaK and NavrátilL. (2019). High inductive magnetic stimuli and their effects on mesenchymal stromal cells, dendritic cells, and fibroblasts. Physiol Res, 68:S433–s443.
121.
ZhangY, YanJ, XuH, YangY, LiW, WuH and LiuC. (2018). Extremely low frequency electromagnetic fields promote mesenchymal stem cell migration by increasing intracellular Ca(2+) and activating the FAK/Rho GTPases signaling pathways in vitro. Stem Cell Res Ther, 9:143.
122.
RobinsonST, DouglasAM, ChadidT, KuoK, RajabalanA, LiH, CoplandIB, BarkerTH, GalipeauJ and BrewsterLP. (2016). A novel platelet lysate hydrogel for endothelial cell and mesenchymal stem cell-directed neovascularization. Acta Biomater, 36:86–98.
123.
RustadKC, WongVW, SorkinM, GlotzbachJP, MajorMR, RajadasJ, LongakerMT and GurtnerGC. (2012). Enhancement of mesenchymal stem cell angiogenic capacity and stemness by a biomimetic hydrogel scaffold. Biomaterials, 33:80–90.
124.
ChenY, LiC, LiC, ChenJ, LiY, XieH, LinC, FanM, GuoY, et al. (2020). Tailorable hydrogel improves retention and cardioprotection of intramyocardial transplanted mesenchymal stem cells for the treatment of acute myocardial infarction in mice. J Am Heart Assoc, 9:e013784.
125.
GaoL, YiM, XingM, LiH, ZhouY, XuQ, ZhangZ, WenZ and ChangJ. (2020). In situ activated mesenchymal stem cells (MSCs) by bioactive hydrogels for myocardial infarction treatment. J Mater Chem B, 8:7713–7722.
126.
YaoY, YangL, FengLF, YueZW, ZhaoNH, LiZ and HeZX. (2020). IGF-1C domain-modified hydrogel enhanced the efficacy of stem cells in the treatment of AMI. Stem Cell Res Ther, 11:136.
127.
LvK, LiQ, ZhangL, WangY, ZhongZ, ZhaoJ, LinX, WangJ, ZhuK, et al. (2019). Incorporation of small extracellular vesicles in sodium alginate hydrogel as a novel therapeutic strategy for myocardial infarction. Theranostics, 9:7403–7416.
ParkTY, JeonEY, KimHJ, ChoiBH and ChaHJ. (2019). Prolonged cell persistence with enhanced multipotency and rapid angiogenesis of hypoxia pre-conditioned stem cells encapsulated in marine-inspired adhesive and immiscible liquid micro-droplets. Acta Biomater, 86:257–268.
130.
ParkTY, J-m Oh, ChoJS, SimSB, LeeJ and ChaHJ. (2020). Stem cell-loaded adhesive immiscible liquid for regeneration of myocardial infarction. J Control Release, 321:602–615.
131.
BlondiauxE, PidialL, AutretG, RahmiG, BalvayD, AudureauE, WilhelmC, GuerinCL, BrunevalP, et al. (2017). 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, 11:3417–3427.
132.
YangJ, ZhouW, ZhengW, MaY, LinL, TangT, LiuJ, YuJ, ZhouX and HuJ. (2007). Effects of myocardial transplantation of marrow mesenchymal stem cells transfected with vascular endothelial growth factor for the improvement of heart function and angiogenesis after myocardial infarction. Cardiology, 107:17–29.
133.
ZhaoL, LiuX, ZhangY, LiangX, DingY, XuY, FangZ and ZhangF. (2016). Enhanced cell survival and paracrine effects of mesenchymal stem cells overexpressing hepatocyte growth factor promote cardioprotection in myocardial infarction. Exp Cell Res, 344:30–39.
134.
LinM, LiuX, ZhengH, HuangX, WuY, HuangA, ZhuH, HuY, MaiW and HuangY. (2020). IGF-1 enhances BMSC viability, migration, and anti-apoptosis in myocardial infarction via secreted frizzled-related protein 2 pathway. Stem Cell Res Ther, 11:22.
135.
HaiderH, JiangS, IdrisNM and AshrafM. (2008). IGF-1-overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-1alpha/CXCR4 signaling to promote myocardial repair. Circ Res, 103:1300–1308.
136.
XueX, LiuY, ZhangJ, LiuT, YangZ, and WangH. (2015). Bcl-xL genetic modification enhanced the therapeutic efficacy of mesenchymal stem cell transplantation in the treatment of heart infarction. Stem Cells Int, 2015:176409.
137.
TangJ, WangJ, YangJ, KongX, ZhengF, GuoL, ZhangL and HuangY. (2009). Mesenchymal stem cells over-expressing SDF-1 promote angiogenesis and improve heart function in experimental myocardial infarction in rats. Eur J Cardiothorac Surg, 36:644–650.
138.
ZhaoSL, ZhangYJ, LiMH, ZhangXL and ChenSL. (2014). Mesenchymal stem cells with overexpression of midkine enhance cell survival and attenuate cardiac dysfunction in a rat model of myocardial infarction. Stem Cell Res Ther, 5:37.
139.
HeJG, LiHR, HanJX, LiBB, YanD, LiHY, WangP and LuoY. (2018). GATA-4-expressing mouse bone marrow mesenchymal stem cells improve cardiac function after myocardial infarction via secreted exosomes. Sci Rep, 8:9047.
GnecchiM, HeH, NoiseuxN, LiangOD, ZhangL, MorelloF, MuH, MeloLG, PrattRE, IngwallJS and DzauVJ. (2006). Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J, 20:661–669.
142.
MaJ, ZhaoY, SunL, SunX, ZhaoX, SunX, QianH, XuW and ZhuW. (2017). Exosomes derived from akt-modified human umbilical cord mesenchymal stem cells improve cardiac regeneration and promote angiogenesis via activating platelet-derived growth factor D. Stem Cells Transl Med, 6:51–59.
143.
PanQ, WangY, LanQ, WuW, LiZ, MaX and YuL. (2019). Exosomes Derived from mesenchymal stem cells ameliorate hypoxia/reoxygenation-injured ECs via transferring MicroRNA-126. Stem Cells Int, 2019:2831756.
144.
ChenJJ and ZhouSH. (2011). Mesenchymal stem cells overexpressing MiR-126 enhance ischemic angiogenesis via the AKT/ERK-related pathway. Cardiol J, 18:675–681.
145.
MaT, ChenY, ChenY, MengQ, SunJ, ShaoL, YuY, HuangH, HuY, et al. (2018). MicroRNA-132, Delivered by mesenchymal stem cell-derived exosomes, promote angiogenesis in myocardial infarction. Stem Cells Int, 2018:3290372.
146.
BlindJE, McLeodEN and CampbellKJ. (2019). Viral-mediated gene therapy and genetically modified therapeutics: a primer on biosafety handling for the health-system pharmacist. Am J Health Syst Pharm, 76:795–802.
147.
WuZ, ChenG, ZhangJ, HuaY, LiJ, LiuB, HuangA, LiH, ChenM and OuC. (2017). Treatment of myocardial infarction with gene-modified mesenchymal stem cells in a small molecular hydrogel. Sci Rep, 7:15826.
