Heart, Lung and Circulation

Bone Marrow Mesenchymal Stem Cells for Heart Failure Treatment: A Systematic Review and Meta-Analysis

Published:March 03, 2023DOI:


      Bone marrow-derived mesenchymal stem cells (BM-MSCs) are the most well-studied and characterised stem cell types. This review was undertaken of the current available phase II/III randomised clinical trials (RCTs) that delivered BM-MSCs to treat patients with cardiomyopathy, and to assess their performance.


      The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were followed during the systematic review and meta-analysis. Eligible studies were reviewed, and their data charted. To assess the efficacy of BM-MSCs, the outcome was improvement in left ventricular ejection fraction (LVEF) and 6-minute walking distance (6MWD).


      The pooled weighted mean difference (WMD) showed that BM-MSCs treatment improved the 6MWD by 27.86 m (95% CI 0.11–55.6 m) compared with the control groups. The pooled WMD showed that BM-MSCs treatment improved the LVEF by 6.37% (95% CI 5.48%–7.26%) compared with the control groups.


      BM-MSCs treatment is an effective intervention for managing patients with heart failure, but it requires larger and more robust clinical trials to support its routine use in clinics.


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        • Tsao C.W.
        • Aday A.W.
        • Almarzooq Z.I.
        • Alonso A.
        • Beaton A.Z.
        • Bittencourt M.S.
        • et al.
        Heart disease and stroke statistics-2022 update: A report from the American Heart Association.
        Circulation. 2022; 145: e153-e639
        • Yancy C.W.
        • Jessup M.
        • Bozkurt B.
        • Butler J.
        • Casey Jr., D.E.
        • Drazner M.H.
        • et al.
        2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
        J Am Coll Cardiol. 2013; 62: e147-e239
        • Marín-García J.
        Cell death in the pathogenesis and progression of heart failure.
        Heart Failure Rev. 2016; 21: 117-121
        • Yutzey K.E.
        Cardiomyocyte proliferation: teaching an old dogma new tricks.
        Circ Res. 2017; 120: 627-629
        • Al-Khani A.M.
        • Khalifa M.A.
        • Haider K.H.
        Mesenchymal stem cells for cardiac repair.
        in: Haider K.H. Handbook of Stem Cell Therapy. Springer Nature Singapore, Singapore2022: 1-53
        • Tompkins B.A.
        • Balkan W.
        • Winkler J.
        • Gyöngyösi M.
        • Goliasch G.
        • Fernández-Avilés F.
        • et al.
        Preclinical studies of stem cell therapy for heart disease.
        Circ Res. 2018; 122: 1006-1020
        • Haider H.
        • Ashraf M.
        Bone marrow stem cell transplantation for cardiac repair.
        Am J Physiol Heart Circ Physiol. 2005; 288: H2557-H2567
        • Aslam M.
        • Husnain Haider K.
        in: Haider K.H. Adrenomedullins and their emerging role in regenerative medicine stem cells: from myth to reality and evolving. De Gruyter, 2019: 145-165
        • Haider K.H.
        Bone marrow cell therapy, and cardiac reparability: better cell characterization will enhance clinical success.
        Regen Med. 2018; 13: 457-475
        • Hamano K.
        • Nishida M.
        • Hirata K.
        • Mikamo A.
        • Li T.S.
        • Harada M.
        • et al.
        Local implantation of autologous bone marrow cells for therapeutic angiogenesis in patients with ischemic heart disease: clinical trial and preliminary results.
        Jpn Circ J. 2001; 65: 845-847
        • Rodríguez-Fuentes D.E.
        • Fernández-Garza L.E.
        • Samia-Meza J.A.
        • Barrera-Barrera S.A.
        • Caplan A.I.
        • Barrera-Saldaña H.A.
        Mesenchymal stem cells current clinical applications: a systematic review.
        Arch Med Res. 2021; 52: 93-101
        • Yagyu T.
        • Yasuda S.
        • Nagaya N.
        • Doi K.
        • Nakatani T.
        • Satomi K.
        • et al.
        Long-term results of intracardiac mesenchymal stem cell transplantation in patients with cardiomyopathy.
        Circ J. 2019; 83: 1590-1599
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        Ann Intern Med. 2009; 151 (264-9, w64)
        • Drevon D.
        • Fursa S.R.
        • Malcolm A.L.
        Intercoder reliability and validity of WebPlotDigitizer in extracting graphed data.
        Behav Modif. 2017; 41: 323-339
        • Jadad A.R.
        • Moore R.A.
        • Carroll D.
        • Jenkinson C.
        • Reynolds D.J.
        • Gavaghan D.J.
        • et al.
        Assessing the quality of reports of randomized clinical trials: is blinding necessary?.
        Control Clin Trials. 1996; 17: 1-12
        • Enright P.L.
        The six-minute walk test.
        Respir Care. 2003; 48: 783-785
        • Higgins J.P.
        • Thompson S.G.
        • Deeks J.J.
        • Altman D.G.
        Measuring inconsistency in meta-analyses.
        BMJ (Clin Res Ed). 2003; 327: 557-560
        • Furuya-Kanamori L.
        • Barendregt J.J.
        • Doi S.A.R.
        A new improved graphical and quantitative method for detecting bias in meta-analysis.
        Int J Evid Based Healthc. 2018; 16: 195-203
        • Hare J.M.
        • Fishman J.E.
        • Gerstenblith G.
        • DiFede Velazquez D.L.
        • Zambrano J.P.
        • Suncion V.Y.
        • et al.
        Comparison of allogeneic vs autologous bone marrow–derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial.
        JAMA. 2012; 308: 2369-2379
        • Perin E.C.
        • Borow K.M.
        • Silva G.V.
        • DeMaria A.N.
        • Marroquin O.C.
        • Huang P.P.
        • et al.
        A Phase II dose-escalation study of allogeneic mesenchymal precursor cells in patients with ischemic or nonischemic heart failure.
        Circ Res. 2015; 117: 576-584
        • Bartunek J.
        • Behfar A.
        • Dolatabadi D.
        • Vanderheyden M.
        • Ostojic M.
        • Dens J.
        • et al.
        Cardiopoietic stem cell therapy in heart failure: the C-CURE (Cardiopoietic stem Cell therapy in heart failURE) multicenter randomized trial with lineage-specified biologics.
        J Am Coll Cardiol. 2013; 61: 2329-2338
        • Mathiasen A.B.
        • Qayyum A.A.
        • Jørgensen E.
        • Helqvist S.
        • Fischer-Nielsen A.
        • Kofoed K.F.
        • et al.
        Bone marrow-derived mesenchymal stromal cell treatment in patients with severe ischaemic heart failure: a randomized placebo-controlled trial (MSC-HF trial).
        Eur Heart J. 2015; 36: 1744-1753
        • Heldman A.W.
        • DiFede D.L.
        • Fishman J.E.
        • Zambrano J.P.
        • Trachtenberg B.H.
        • 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
        • Xiao W.
        • Guo S.
        • Gao C.
        • Dai G.
        • Gao Y.
        • Li M.
        • et al.
        A randomized comparative study on the efficacy of intracoronary infusion of autologous bone marrow mononuclear cells and mesenchymal stem cells in patients with dilated cardiomyopathy.
        Int Heart J. 2017; 58: 238-244
        • Shen T.
        • Xia L.
        • Dong W.
        • Wang J.
        • Su F.
        • Niu S.
        • et al.
        A systematic review and meta-analysis: safety and efficacy of mesenchymal stem cells therapy for heart failure.
        Curr Stem Cell Res Ther. 2021; 16: 354-365
        • Fan M.
        • Huang Y.
        • Chen Z.
        • Xia Y.
        • Chen A.
        • Lu D.
        • et al.
        Efficacy of mesenchymal stem cell therapy in systolic heart failure: a systematic review and meta-analysis.
        Stem Cell Res Ther. 2019; 10: 150
        • Wright A.
        • Arthaud-Day M.L.
        • Weiss M.L.
        Therapeutic use of mesenchymal stromal cells: the need for inclusive characterization guidelines to accommodate all tissue sources and species.
        Front Cell Dev Biol. 2021; 9
        • Wang Y.
        • Xu F.
        • Ma J.
        • Shi J.
        • Chen S.
        • Liu Z.
        • et al.
        Effect of stem cell transplantation on patients with ischemic heart failure: a systematic review and meta-analysis of randomized controlled trials.
        Stem Cell Res Ther. 2019; 10: 125
        • Tripathi A.
        • Khan M.S.
        • Khan A.R.
        • Vaughn V.M.
        • Bolli R.
        Cell therapy for nonischemic dilated cardiomyopathy: a systematic review and meta-analysis of randomized controlled trials.
        Stem Cells Transl Med. 2021; 10: 1394-1405
        • Xia L.
        • Zeng L.
        • Pan J.
        • Ding Y.
        Effects of stem cells on non-ischemic cardiomyopathy: a systematic review and meta-analysis of randomized controlled trials.
        Cytotherapy. 2020; 22: 699-711
        • Gyöngyösi M.
        • Wojakowski W.
        • Lemarchand P.
        • Lunde K.
        • Tendera M.
        • Bartunek J.
        • et al.
        Meta-Analysis of Cell-based CaRdiac stUdiEs (ACCRUE) in patients with acute myocardial infarction based on individual patient data.
        Circ Res. 2015; 116: 1346-1360
        • Attar A.
        • Bahmanzadegan Jahromi F.
        • Kavousi S.
        • Monabati A.
        • Kazemi A.
        Mesenchymal stem cell transplantation after acute myocardial infarction: a meta-analysis of clinical trials.
        Stem Cell Res Ther. 2021; 12: 600
        • Giannitsi S.
        • Bougiakli M.
        • Bechlioulis A.
        • Kotsia A.
        • Michalis L.K.
        • Naka K.K.
        6-minute walking test: a useful tool in the management of heart failure patients.
        Ther Adv Cardiovasc Dis. 2019; 13 (1753944719870084)
        • Olsson L.G.
        • Swedberg K.
        • Clark A.L.
        • Witte K.K.
        • Cleland J.G.F.
        Six minute corridor walk test as an outcome measure for the assessment of treatment in randomized, blinded intervention trials of chronic heart failure: a systematic review.
        Eur Heart J. 2005; 26: 778-793
        • Lancaster L.
        • Fieuw A.
        • Meulemans J.
        • Ford P.
        • Nathan S.D.
        Standardization of the 6-min walk test in clinical trials of idiopathic pulmonary fibrosis.
        Contemp Clin Trials. 2021; 100: 106227
        • Arslan S.
        • Erol M.K.
        • Gundogdu F.
        • Sevimli S.
        • Aksakal E.
        • Senocak H.
        • et al.
        Prognostic value of 6-minute walk test in stable outpatients with heart failure.
        Tex Heart Inst J. 2007; 34: 166-169
        • Ferreira J.P.
        • Duarte K.
        • Graves T.L.
        • Zile M.R.
        • Abraham W.T.
        • Weaver F.A.
        • et al.
        Natriuretic peptides, 6-min walk test, and quality-of-life questionnaires as clinically meaningful endpoints in HF trials.
        J Am Coll Cardiol. 2016; 68: 2690-2707
        • Jeong H.
        • Yim H.W.
        • Park H.J.
        • Cho Y.
        • Hong H.
        • Kim N.J.
        • et al.
        Mesenchymal stem cell therapy for ischemic heart disease: systematic review and meta-analysis.
        Int J Stem Cells. 2018; 11: 1-12
        • Florea V.
        • Rieger A.C.
        • DiFede D.L.
        • El-Khorazaty J.
        • Natsumeda M.
        • Banerjee M.N.
        • et al.
        Dose comparison study of allogeneic mesenchymal stem cells in patients with ischemic cardiomyopathy (The TRIDENT Study).
        Circ Res. 2017; 121: 1279-1290
      1. Shahid MS, Lasheen W, Haider KH. Modest outcome of clinical trials with bone marrow cells for myocardial repair: is the autologous source of cells the prime culprit? J Thorac Dis. 2916;8(10):E1371–E1374.

        • Haider K.H.
        Hematopoietic stem cell transplantation: the quality matters.
        J Stem Cell Res Ther. 2017; 7: 6
        • Haider K.H.
        The aging stem cells and cardiac reparability: lesson learnt from clinical studies is that old is not always gold.
        Regen Med. 2018; 13: 457-475