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Pluripotent stem cell-derived mesenchymal stromal cells improve cardiac function and vascularity after myocardial infarction

Published:September 27, 2021DOI:https://doi.org/10.1016/j.jcyt.2021.07.016

      Abstract

      Background aims

      Mesenchymal stromal cells (MSCs) have been shown to improve cardiac function after injury and are the subject of ongoing clinical trials. In this study, the authors tested the cardiac regenerative potential of an induced pluripotent stem cell-derived MSC (iPSC-MSC) population (Cymerus MSCs) in a rat model of myocardial ischemia-reperfusion (I/R). Furthermore, the authors compared this efficacy with bone marrow-derived MSCs (BM-MSCs), which are the predominant cell type in clinical trials.

      Methods

      Four days after myocardial I/R injury, rats were randomly assigned to (i) a Cymerus MSC group (n = 15), (ii) a BM-MSC group (n = 15) or (iii) a vehicle control group (n = 14). For cell-treated animals, a total of 5 × 106 cells were injected at three sites within the infarcted left ventricular (LV) wall.

      Results

      One month after cell transplantation, Cymerus MSCs improved LV function (assessed by echocardiography) compared with vehicle and BM-MSCs. Interestingly, Cymerus MSCs enhanced angiogenesis without sustained engraftment or significant impact on infarct scar size. Suggesting safety, Cymerus MSCs had no effect on inducible tachycardia or the ventricular scar heterogeneity that provides a substrate for cardiac re-entrant circuits.

      Conclusions

      The authors here demonstrate that intra-myocardial administration of iPSC-MSCs (Cymerus MSCs) provide better therapeutic effects compared with conventional BM-MSCs in a rodent model of myocardial I/R. Because of its manufacturing scalability, iPSC-MSC therapy offers an exciting opportunity for an “off-the-shelf” stem cell therapy for cardiac repair.

      Key Words

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      References

        • Benjamin EJ
        • Virani SS
        • Callaway CW
        • Chamberlain AM
        • Chang AR
        • Cheng S
        • et al.
        Heart Disease and Stroke Statistics—2018 Update: A Report From the American Heart Association.
        Circulation. 2018; 137: e67-492
        • ST Ji
        • Kim H
        • Yun J
        • Chung JS
        • Kwon S-M.
        Promising Therapeutic Strategies for Mesenchymal Stem Cell-Based Cardiovascular Regeneration: From Cell Priming to Tissue Engineering.
        Stem Cells Int. 2017; 20173945403
        • Perin EC
        • Willerson JT
        • Pepine CJ
        • Henry TD
        • Ellis SG
        • Zhao DXM
        • et al.
        Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial.
        JAMA. 2012; 307: 1717-1726
        • Traverse JH
        • Henry TD
        • Pepine CJ
        • Willerson JT
        • Zhao DXM
        • Ellis SG
        • et al.
        Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: the TIME randomized trial.
        JAMA. 2012; 308: 2380-2389
        • Choudry F
        • Hamshere S
        • Saunders N
        • Veerapen J
        • Bavnbek K
        • Knight C
        • et al.
        A randomized double-blind control study of early intra-coronary autologous bone marrow cell infusion in acute myocardial infarction: the REGENERATE-AMI clinical trial†.
        Eur Heart J. 2016; 37: 256-263
        • Huikuri H V
        • Kervinen K
        • Niemelä M
        • Ylitalo K
        • Säily M
        • Koistinen P
        • et al.
        Effects of intracoronary injection of mononuclear bone marrow cells on left ventricular function, arrhythmia risk profile, and restenosis after thrombolytic therapy of acute myocardial infarction.
        Eur Heart J. 2008; 29: 2723-2732
        • Schächinger V
        • Erbs S
        • Elsässer A
        • Haberbosch W
        • Hambrecht R
        • Hölschermann H
        • et al.
        Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction.
        N Engl J Med. 2006; 355: 1210-1221
        • Lunde K
        • Solheim S
        • Aakhus S
        • Arnesen H
        • Abdelnoor M
        • Egeland T
        • et al.
        Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction.
        N Engl J Med. 2006; 355: 1199-1209
        • Janssens S
        • Dubois C
        • Bogaert J
        • Theunissen K
        • Deroose C
        • Desmet W
        • et al.
        Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial.
        Lancet (London, England). 2006; 367: 113-121
        • Wollert KC
        • Meyer GP
        • Lotz J
        • Ringes-Lichtenberg S
        • Lippolt P
        • Breidenbach C
        • et al.
        Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial.
        Lancet (London, England). 2004; 364: 141-148
        • Sürder D
        • Manka R
        • Lo Cicero V
        • Moccetti T
        • Rufibach K
        • Soncin S
        • et al.
        Intracoronary injection of bone marrow-derived mononuclear cells early or late after acute myocardial infarction: effects on global left ventricular function.
        Circulation. 2013; 127: 1968-1979
        • Wollert KC
        • Meyer GP
        • Müller-Ehmsen J
        • Tschöpe C
        • Bonarjee V
        • Larsen AI
        • et al.
        Intracoronary autologous bone marrow cell transfer after myocardial infarction: the BOOST-2 randomised placebo-controlled clinical trial.
        Eur Heart J. 2017; 38: 2936-2943
        • Karantalis V
        • Schulman IH
        • Balkan W
        • Hare JM.
        Allogeneic cell therapy: a new paradigm in therapeutics.
        Circ Res. 2015; 116: 12-15
        • Sanina C
        • Hare JM.
        Mesenchymal Stem Cells as a Biological Drug for Heart Disease.
        Circ Res. 2015; 117: 229-233
        • Hare JM
        • Fishman JE
        • Gerstenblith G
        • DiFede Velazquez DL
        • Zambrano JP
        • Suncion VY
        • et al.
        Comparison of Allogeneic vs Autologous Bone Marrow–Derived Mesenchymal Stem Cells Delivered by Transendocardial Injection in Patients With Ischemic Cardiomyopathy.
        JAMA. 2012; 308: 2369
        • Chen G
        • Gulbranson DR
        • Hou Z
        • Bolin JM
        • Ruotti V
        • Probasco MD
        • et al.
        Chemically defined conditions for human iPSC derivation and culture.
        Nat Methods. 2011; 8: 424-429
        • Vodyanik MA
        • Yu J
        • Zhang X
        • Tian S
        • Stewart R
        • Thomson JA
        • et al.
        A mesoderm-derived precursor for mesenchymal stem and endothelial cells.
        Cell Stem Cell. 2010; 7: 718-729
        • Bloor AJC
        • Patel A
        • Griffin JE
        • Gilleece MH
        • Radia R
        • Yeung DT
        • et al.
        Production, safety and efficacy of iPSC-derived mesenchymal stromal cells in acute steroid-resistant graft versus host disease: a phase I, multicenter, open-label, dose-escalation study.
        Nat Med. 2020; 26: 1720-1725
        • Ozay EI
        • Vijayaraghavan J
        • Gonzalez-Perez G
        • Shanthalingam S
        • Sherman HL
        • Garrigan DT
        • et al.
        CymerusTM iPSC-MSCs significantly prolong survival in a pre-clinical, humanized mouse model of Graft-vs-host disease.
        Stem Cell Res. 2019; 35101401
        • Weinberg L
        • Collins N
        • Van Mourik K
        • Tan C
        • Bellomo R.
        Plasma-Lye 148: A clinical review.
        World J Crit care Med. 2016; 5: 235-250
        • Le TYL
        • Pickett HA
        • Yang A
        • Ho JWK
        • Thavapalachandran S
        • Igoor S
        • et al.
        Enhanced cardiac repair by telomerase reverse transcriptase over-expression in human cardiac mesenchymal stromal cells.
        Sci Rep. 2019; 9: 10579
        • Fernandes S
        • Chong JJH
        • Paige SL
        • Iwata M
        • Torok-Storb B
        • Keller G
        • et al.
        Comparison of Human Embryonic Stem Cell-Derived Cardiomyocytes, Cardiovascular Progenitors, and Bone Marrow Mononuclear Cells for Cardiac Repair.
        Stem Cell Reports. 2015; 5: 753-762
        • Zaman S
        • Narayan A
        • Thiagalingam A
        • Sivagangabalan G
        • Thomas S
        • Ross DL
        • et al.
        Long-Term Arrhythmia-Free Survival in Patients With Severe Left Ventricular Dysfunction and No Inducible Ventricular Tachycardia After Myocardial Infarction.
        Circulation. 2014; 129: 848-854
        • Pouliopoulos J
        • Sivagangabalan G
        • Barry MA
        • Thiagalingam A
        • Huang K
        • Lu J
        • et al.
        Revised non-contact mapping of ventricular scar in a post-infarct ovine model with validation using contact mapping and histology.
        Europace. 2010; 12: 881-889
        • Thavapalachandran S
        • Grieve SM
        • Hume RD
        • Le TYL
        • Raguram K
        • Hudson JE
        • et al.
        Platelet-derived growth factor-AB improves scar mechanics and vascularity after myocardial infarction.
        Sci Transl Med. 2020; 12: eaay2140
        • Quevedo HC
        • Hatzistergos KE
        • Oskouei BN
        • Feigenbaum GS
        • Rodriguez JE
        • Valdes D
        • et al.
        Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity.
        Proc Natl Acad Sci. 2009; 106: 14022-14027
        • Williams AR
        • Trachtenberg B
        • Velazquez DL
        • McNiece I
        • Altman P
        • Rouy D
        • et al.
        Intramyocardial Stem Cell Injection in Patients With Ischemic Cardiomyopathy.
        Circ Res. 2011; 108: 792-796
        • Chong JJH
        • Yang X
        • Don CW
        • Minami E
        • Liu Y-W
        • Weyers JJ
        • et al.
        Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts.
        Nature. 2014; 510: 273-277
        • Shiba Y
        • Gomibuchi T
        • Seto T
        • Wada Y
        • Ichimura H
        • Tanaka Y
        • et al.
        Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts.
        Nature. 2016; 538: 388-391
        • Morellato J
        • Chik W
        • Barry MA
        • Lu J
        • Thiagalingam A
        • Kovoor P
        • et al.
        Quantitative spectral assessment of intracardiac electrogram characteristics associated with post infarct fibrosis and ventricular tachycardia.
        PLoS One. 2018; 13e0204997
        • Galderisi U
        • Giordano A.
        The Gap Between the Physiological and Therapeutic Roles of Mesenchymal Stem Cells.
        Med Res Rev. 2014; 34: 1100-1126
        • Kocher AA
        • Schuster MD
        • Bonaros N
        • Lietz K
        • Xiang G
        • Martens TP
        • et al.
        Myocardial homing and neovascularization by human bone marrow angioblasts is regulated by IL-8/Gro CXC chemokines.
        J Mol Cell Cardiol. 2006; 40: 455-464
        • Kimura K
        • Nagano M
        • Salazar G
        • Yamashita T
        • Tsuboi I
        • Mishima H
        • et al.
        The role of CCL5 in the ability of adipose tissue-derived mesenchymal stem cells to support repair of ischemic regions.
        Stem Cells Dev. 2014; 23: 488-501
        • Watt SM
        • Gullo F
        • van der Garde M
        • Markeson D
        • Camicia R
        • Khoo CP
        • et al.
        The angiogenic properties of mesenchymal stem/stromal cells and their therapeutic potential.
        Br Med Bull. 2013; 108: 25-53
        • Yang X
        • Liaw L
        • Prudovsky I
        • Brooks PC
        • Vary C
        • Oxburgh L
        • et al.
        Fibroblast growth factor signaling in the vasculature.
        Curr Atheroscler Rep. 2015; 17: 509
        • Mayfield AE
        • Kanda P
        • Nantsios A
        • Parent S
        • Mount S
        • Dixit S
        • et al.
        Interleukin-6 Mediates Post-Infarct Repair by Cardiac Explant-Derived Stem Cells.
        Theranostics. 2017; 7: 4850-4861
        • Catar R
        • Witowski J
        • Zhu N
        • Lücht C
        • Derrac Soria A
        Uceda Fernandez J, et al. IL-6 Trans-Signaling Links Inflammation with Angiogenesis in the Peritoneal Membrane.
        J Am Soc Nephrol. 2017; 28: 1188-1199
        • Baker JE
        • Su J
        • Hsu A
        • Shi Y
        • Zhao M
        • Strande JL
        • et al.
        Human thrombopoietin reduces myocardial infarct size, apoptosis, and stunning following ischaemia/reperfusion in rats.
        Cardiovasc Res. 2007; 77: 44-53
        • Kirito K
        • Fox N
        • Komatsu N
        • Kaushansky K
        • Kato T
        • Miyazaki H
        • et al.
        Thrombopoietin enhances expression of vascular endothelial growth factor (VEGF) in primitive hematopoietic cells through induction of HIF-1alpha.
        Blood. 2005; 105: 4258-4263
        • Sang QXA.
        Complex role of matrix metalloproteinases in angiogenesis.
        Cell Res. 1998; 8: 171-177
        • Kretlow JD
        • Jin Y-Q
        • Liu W
        • Zhang W
        • Hong T-H
        • Zhou G
        • et al.
        Donor age and cell passage affects differentiation potential of murine bone marrow-derived stem cells.
        BMC Cell Biol. 2008; 9: 60
        • Wagner W
        • Bork S
        • Horn P
        • Krunic D
        • Walenda T
        • Diehlmann A
        • et al.
        Aging and Replicative Senescence Have Related Effects on Human Stem and Progenitor Cells.
        PLoS One. 4. 2009: e5846 (Jun 9)
        • Yu J
        • Vodyanik MA
        • Smuga-Otto K
        • Antosiewicz-Bourget J
        • Frane JL
        • Tian S
        • et al.
        Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells.
        Science (80- ). 2007; 318: 1917-1920
        • Takahashi K
        • Tanabe K
        • Ohnuki M
        • Narita M
        • Ichisaka T
        • Tomoda K
        • et al.
        Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors.
        Cell. 2007; 131: 861-872
        • Afzal MR
        • Samanta A
        • Shah ZI
        • Jeevanantham V
        • Abdel-Latif A
        • Zuba-Surma EK
        • et al.
        Adult Bone Marrow Cell Therapy for Ischemic Heart Disease.
        Circ Res. 2015; 117 (Aug 28): 558-575
        • Toma C
        • Pittenger MF
        • Cahill KS
        • Byrne BJ
        • Kessler PD.
        Human Mesenchymal Stem Cells Differentiate to a Cardiomyocyte Phenotype in the Adult Murine Heart.
        Circulation. 2002; 105: 93-98
        • Ly HQ
        • Hoshino K
        • Pomerantseva I
        • Kawase Y
        • Yoneyama R
        • Takewa Y
        • et al.
        In vivo myocardial distribution of multipotent progenitor cells following intracoronary delivery in a swine model of myocardial infarction.
        Eur Heart J. 2009; 30: 2861-2868
        • Ward MR
        • Abadeh A
        • Connelly KA.
        Concise Review: Rational Use of Mesenchymal Stem Cells in the Treatment of Ischemic Heart Disease.
        Stem Cells Transl Med. 2018; 7: 543-550
        • Mazhari R
        • Hare JM.
        Mechanisms of action of mesenchymal stem cells in cardiac repair: potential influences on the cardiac stem cell niche.
        Nat Clin Pract Cardiovasc Med. 2007; 1: S21-S26
        • Gnecchi M
        • Zhang Z
        • Ni A
        • Dzau VJ.
        Paracrine Mechanisms in Adult Stem Cell Signaling and Therapy.
        Circ Res. 2008; 103: 1204-1219
        • DiPietro LA
        Angiogenesis and wound repair: when enough is enough.
        J Leukoc Biol. 2016; 100: 979-984
        • Puhl S-L
        • Steffens S.
        Neutrophils in Post-myocardial Infarction Inflammation: Damage vs. Resolution?.
        Front Cardiovasc Med. 2019; 6: 25
        • Arenberg DA
        • Keane MP
        • DiGiovine B
        • Kunkel SL
        • Morris SB
        • Xue YY
        • et al.
        Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer.
        J Clin Invest. 1998; 102: 465-472
        • Seo DW
        • Li H
        • Guedez L
        • Wingfield PT
        • Diaz T
        • Salloum R
        • et al.
        TIMP-2 mediated inhibition of angiogenesis: An MMP-independent mechanism.
        Cell. 2003; 114: 171-180
        • Ferrara N
        • Gerber H-P
        • LeCouter J.
        The biology of VEGF and its receptors.
        Nat Med. 2003; 9: 669-676
        • Catar R
        • Witowski J
        • Zhu N
        • Lücht C
        • Derrac Soria A
        Uceda Fernandez J, et al. IL-6 Trans-Signaling Links Inflammation with Angiogenesis in the Peritoneal Membrane.
        J Am Soc Nephrol. 2017; 28: 1188-1199
        • Fee D
        • Grzybicki D
        • Dobbs M
        • Ihyer S
        • Clotfelter J
        • Macvilay S
        • et al.
        Interleukin 6 promotes vasculogenesis of murine brain microvessel endothelial cells.
        Cytokine. 2000; 12: 655-665
        • Heldman AW
        • DiFede DL
        • Fishman JE
        • Zambrano JP
        • Trachtenberg BH
        • Karantalis V
        • et al.
        Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial.
        JAMA. 2014; 311: 62-73
        • Menasché P
        • Alfieri O
        • Janssens S
        • McKenna W
        • Reichenspurner H
        • Trinquart L
        • et al.
        The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation.
        Circulation. 2008; 117: 1189-1200
        • Fukushima S
        • Varela-Carver A
        • Coppen SR
        • Yamahara K
        • Felkin LE
        • Lee J
        • et al.
        Direct intramyocardial but not intracoronary injection of bone marrow cells induces ventricular arrhythmias in a rat chronic ischemic heart failure model.
        Circulation. 2007; 115: 2254-2261
        • Ramireddy A
        • Brodt CR
        • Mendizabal AM
        • DiFede DL
        • Healy C
        • Goyal V
        • et al.
        Effects of Transendocardial Stem Cell Injection on Ventricular Proarrhythmia in Patients with Ischemic Cardiomyopathy: Results from the POSEIDON and TAC-HFT Trials.
        Stem Cells Transl Med. 2017; 6: 1366-1372
        • Samanta A
        • Kaja AK
        • Afzal MR
        • Zuba-Surma EK
        • Dawn B
        Bone marrow cells for heart repair: clinical evidence and perspectives.
        Minerva Cardioangiol. 2017; 65: 299-313
        • Chong JJH
        • Murry CE.
        Cardiac regeneration using pluripotent stem cells—progression to large animal models.
        Stem Cell Res. 2014; 13: 654-665
        • Frangogiannis NG.
        The inflammatory response in myocardial injury, repair, and remodelling.
        Nat Rev Cardiol. 2014; 11: 255-265
        • Frangogiannis NG.
        Chemokines in the ischemic myocardium: from inflammation to fibrosis.
        Inflamm Res. 2004; 53: 585-595
        • Fomovsky GM
        • Clark SA
        • Parker KM
        • Ailawadi G
        • Holmes JW.
        Anisotropic Reinforcement of Acute Anteroapical Infarcts Improves Pump Function.
        Circ Hear Fail. 2012; 5: 515-522
        • Fomovsky GM
        • Rouillard AD
        • Holmes JW.
        Regional mechanics determine collagen fiber structure in healing myocardial infarcts.
        J Mol Cell Cardiol. 2012; 52: 1083-1090
        • Voorhees AP
        • Han H-C.
        A model to determine the effect of collagen fiber alignment on heart function post myocardial infarction.
        Theor Biol Med Model. 2014; 11: 6
        • Caggiano LR
        • Lee J-J
        • Holmes JW.
        Surgical reinforcement alters collagen alignment and turnover in healing myocardial infarcts.
        Am J Physiol Circ Physiol. 2018; 315: H1041-H1050