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ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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Review Article

Stem Cell-based Therapies in Cardiovascular Diseases: From Pathophysiology to Clinical Outcomes

Author(s): Charalampos Papastamos*, Alexios S. Antonopoulos*, Spyridon Simantiris, Nikolaos Koumallos, Panagiotis Theofilis, Marios Sagris, Konstantinos Tsioufis, Emmanuel Androulakis and Dimitris Tousoulis

Volume 29, Issue 35, 2023

Published on: 02 October, 2023

Page: [2795 - 2801] Pages: 7

DOI: 10.2174/1381612829666230828102130

Price: $65

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Abstract

Over 20 years of intensified research in the field of stem cells brought about unprecedented possibilities in treating heart diseases. The investigators were initially fascinated by the idea of regenerating the lost myocardium and replacing it with new functional cardiomyocytes, but this was extremely challenging. However, the multifactorial effects of stem cell-based therapies beyond mere cardiomyocyte generation, caused by paracrine signaling, would open up new possibilities in treating cardiovascular diseases. To date, there is a strong body of evidence that the anti-inflammatory, anti-apoptotic, and immunomodulatory effects of stem cell therapy may alleviate atherosclerosis progression. In the present review, our objective is to provide a brief overview of the stem cell-based therapeutic options. We aim to delineate the pathophysiological mechanisms of their beneficial effects in cardiovascular diseases especially in coronary artery disease and to highlight some conclusions from important clinical studies in the field of regenerative medicine in cardiovascular diseases and how we could further move onwards.

Keywords: Stem cells, stem cell-based therapies in atherosclerosis, pathophysiological mechanisms of stem-cell action, stem cells in clinical studies, stem cell in coronary artery disease, stem cell paracrine signaling.

« Previous Next »
[1]
Beltrami AP, Barlucchi L, Torella D, et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003; 114(6): 763-76.
[http://dx.doi.org/10.1016/S0092-8674(03)00687-1] [PMID: 14505575]
[2]
Collins LR, Priest C, Caras I, Littman N, Kadyk L. Proceedings: Moving toward cell-based therapies for heart disease. Stem Cells Transl Med 2015; 4(8): 863-7.
[http://dx.doi.org/10.5966/sctm.2015-0118] [PMID: 26136501]
[3]
Bolli R, Solankhi M, Tang XL, Kahlon A. Cell therapy in patients with heart failure: A comprehensive review and emerging concepts. Cardiovasc Res 2022; 118(4): 951-76.
[http://dx.doi.org/10.1093/cvr/cvab135] [PMID: 33871588]
[4]
Braunwald E. Cell-based therapy in cardiac regeneration. Circ Res 2018; 123(2): 132-7.
[http://dx.doi.org/10.1161/CIRCRESAHA.118.313484] [PMID: 29976683]
[5]
Dow J, Simkhovich B, Kedes L, Kloner R. Washout of transplanted cells from the heart: A potential new hurdle for cell transplantation therapy. Cardiovasc Res 2005; 67(2): 301-7.
[http://dx.doi.org/10.1016/j.cardiores.2005.04.011] [PMID: 15907822]
[6]
Perin EC, Borow KM, Henry TD, et al. Randomized trial of targeted transendocardial mesenchymal precursor cell therapy in patients with heart failure. J Am Coll Cardiol 2023; 81(9): 849-63.
[http://dx.doi.org/10.1016/j.jacc.2022.11.061] [PMID: 36858705]
[7]
Zhang J, Bolli R, Garry DJ, et al. Basic and translational research in cardiac repair and regeneration. J Am Coll Cardiol 2021; 78(21): 2092-105.
[http://dx.doi.org/10.1016/j.jacc.2021.09.019] [PMID: 34794691]
[8]
Ridker PM, Everett BM, Thuren T, et al. Anti-inflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017; 377(12): 1119-31.
[http://dx.doi.org/10.1056/NEJMoa1707914] [PMID: 28845751]
[9]
Davani S, Deschaseaux F, Chalmers D, Tiberghien P, Kantelip J. Can stem cells mend a broken heart? Cardiovasc Res 2005; 65(2): 305-16.
[http://dx.doi.org/10.1016/j.cardiores.2004.10.037] [PMID: 15639469]
[10]
Menasché P, Hagège AA, Scorsin M, et al. Myoblast transplantation for heart failure. Lancet 2001; 357(9252): 279-80.
[http://dx.doi.org/10.1016/S0140-6736(00)03617-5] [PMID: 11214133]
[11]
Yan W, Lin C, Guo Y, et al. N-Cadherin overexpression mobilizes the protective effects of mesenchymal stromal cells against ischemic heart injury through a β-catenin-dependent manner. Circ Res 2020; 126(7): 857-74.
[http://dx.doi.org/10.1161/CIRCRESAHA.119.315806] [PMID: 32079489]
[12]
Gwizdala A, Rozwadowska N, Kolanowski TJ, et al. Safety, feasibility and effectiveness of first in-human administration of muscle- derived stem/progenitor cells modified with connexin-43 gene for treatment of advanced chronic heart failure. Eur J Heart Fail 2017; 19(1): 148-57.
[http://dx.doi.org/10.1002/ejhf.700] [PMID: 28052545]
[13]
Kermani F, Mosqueira M, Peters K, et al. Membrane remodelling triggers maturation of excitation-contraction coupling in 3D-shaped human-induced pluripotent stem cell-derived cardiomyocytes. Basic Res Cardiol 2023; 118(1): 13.
[http://dx.doi.org/10.1007/s00395-023-00984-5] [PMID: 36988697]
[14]
Hirt MN, Hansen A, Eschenhagen T. Cardiac tissue engineering: State of the art. Circ Res 2014; 114(2): 354-67.
[http://dx.doi.org/10.1161/CIRCRESAHA.114.300522] [PMID: 24436431]
[15]
Wysoczynki M, Khan A, Bolli R. New paradigms in cell therapy. Circ Res 2018; 123(2): 138-58.
[http://dx.doi.org/10.1161/CIRCRESAHA.118.313251] [PMID: 29976684]
[16]
Braunwald E. Cardiac cell therapy: A call for action. Eur Heart J 2022; 43(25): 2352-3.
[http://dx.doi.org/10.1093/eurheartj/ehac188] [PMID: 35417529]
[17]
Martens TP, See F, Schuster MD, et al. Mesenchymal lineage precursor cells induce vascular network formation in ischemic myocardium. Nat Clin Pract Cardiovasc Med 2006; 3(S1): S18-22.
[http://dx.doi.org/10.1038/ncpcardio0404] [PMID: 16501624]
[18]
Dooley LM, Abdalmula A, Washington EA, et al. Effect of mesenchymal precursor cells on the systemic inflammatory response and endothelial dysfunction in an ovine model of collagen-induced arthritis. PLoS One 2015; 10(5): e0124144.
[http://dx.doi.org/10.1371/journal.pone.0124144] [PMID: 25950840]
[19]
Wang S, Hu S, Zhang Q, Xia A, Jiang Z, Chen X. Mesenchymal stem cells stabilize atherosclerotic vulnerable plaque by anti-inflammatory properties. PLoS One 2015; 10(8): e0136026.
[http://dx.doi.org/10.1371/journal.pone.0136026] [PMID: 26288013]
[20]
Zhang X, Huang F, Li W, et al. Human gingiva-derived mesenchymal stem cells modulate monocytes/macrophages and alleviate atherosclerosis. Front Immunol 2018; 9: 878.
[http://dx.doi.org/10.3389/fimmu.2018.00878] [PMID: 29760701]
[21]
Wang J, Gong M, Zuo S, et al. WNT11-conditioned medium promotes angiogenesis through the activation of non-canonical WNT-PKC-JNK signaling pathway. Genes 2020; 11(11): 1277.
[http://dx.doi.org/10.3390/genes11111277] [PMID: 33137935]
[22]
El Harane N, Kervadec A, Bellamy V, et al. Acellular therapeutic approach for heart failure: In vitro production of extracellular vesicles from human cardiovascular progenitors. Eur Heart J 2018; 39(20): 1835-47.
[http://dx.doi.org/10.1093/eurheartj/ehy012] [PMID: 29420830]
[23]
Libby P. The changing landscape of atherosclerosis. Nature 2021; 592(7855): 524-33.
[http://dx.doi.org/10.1038/s41586-021-03392-8] [PMID: 33883728]
[24]
Falk E. Pathogenesis of atherosclerosis. J Am Coll Cardiol 2006; 47(S8): C7-C12.
[http://dx.doi.org/10.1016/j.jacc.2005.09.068] [PMID: 16631513]
[25]
Yang H, Zhang N, Okoro E, Guo Z. Transport of apolipoprotein b-containing lipoproteins through endothelial cells is associated with apolipoprotein e-carrying HDL-like particle formation. Int J Mol Sci 2018; 19(11): 3593.
[http://dx.doi.org/10.3390/ijms19113593] [PMID: 30441770]
[26]
McLaren JE, Michael DR, Ashlin TG, Ramji DP. Cytokines, macrophage lipid metabolism and foam cells: Implications for cardiovascular disease therapy. Prog Lipid Res 2011; 50(4): 331-47.
[http://dx.doi.org/10.1016/j.plipres.2011.04.002] [PMID: 21601592]
[27]
Tabas I, Williams KJ, Borén JJC. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: Update and therapeutic implications. Circulation 2007; 116(16): 1832-44.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.106.676890]
[28]
Moore KJ, Sheedy FJ, Fisher EA. Macrophages in atherosclerosis: A dynamic balance. Nat Rev Immunol 2013; 13(10): 709-21.
[http://dx.doi.org/10.1038/nri3520] [PMID: 23995626]
[29]
Medina I, Cougoule C, Drechsler M, et al. Hck/Fgr kinase deficiency reduces plaque growth and stability by blunting monocyte recruitment and intraplaque motility. Circulation 2015; 132(6): 490-501.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.114.012316] [PMID: 26068045]
[30]
Eshghjoo S, Kim DM, Jayaraman A, Sun Y, Alaniz RC. Macrophage polarization in atherosclerosis. Genes 2022; 13(5): 756.
[http://dx.doi.org/10.3390/genes13050756] [PMID: 35627141]
[31]
Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature 2011; 473(7347): 317-25.
[http://dx.doi.org/10.1038/nature10146] [PMID: 21593864]
[32]
Saigusa R, Winkels H, Ley K. T cell subsets and functions in atherosclerosis. Nat Rev Cardiol 2020; 17(7): 387-401.
[http://dx.doi.org/10.1038/s41569-020-0352-5] [PMID: 32203286]
[33]
Grootaert MOJ, Bennett MR. Vascular smooth muscle cells in atherosclerosis: Time for a re-assessment. Cardiovasc Res 2021; 117(11): 2326-39.
[http://dx.doi.org/10.1093/cvr/cvab046] [PMID: 33576407]
[34]
Finn AV, Nakano M, Narula J, Kolodgie FD, Virmani R. Concept of vulnerable/unstable plaque. Arterioscler Thromb Vasc Biol 2010; 30(7): 1282-92.
[http://dx.doi.org/10.1161/ATVBAHA.108.179739] [PMID: 20554950]
[35]
Grover SP, Mackman N. Tissue factor in atherosclerosis and atherothrombosis. Atherosclerosis 2020; 307: 80-6.
[http://dx.doi.org/10.1016/j.atherosclerosis.2020.06.003] [PMID: 32674807]
[36]
Salvolini E, Orciani M, Vignini A, Mattioli-Belmonte M, Mazzanti L, Di Primio R. Skin-derived mesenchymal stem cells (S-MSCs) induce endothelial cell activation by paracrine mechanisms. Exp Dermatol 2010; 19(9): 848-50.
[http://dx.doi.org/10.1111/j.1600-0625.2010.01104.x] [PMID: 20629738]
[37]
Lin YL, Yet SF, Hsu YT, Wang GJ, Hung SC. Mesenchymal stem cells ameliorate atherosclerotic lesions via restoring endothelial function. Stem Cells Transl Med 2015; 4(1): 44-55.
[http://dx.doi.org/10.5966/sctm.2014-0091] [PMID: 25504897]
[38]
Yuan Y, Shi M, Li L, et al. Mesenchymal stem cell-conditioned media ameliorate diabetic endothelial dysfunction by improving mitochondrial bioenergetics via the Sirt1/AMPK/PGC-1α pathway. Clin Sci 2016; 130(23): 2181-98.
[http://dx.doi.org/10.1042/CS20160235] [PMID: 27613156]
[39]
Frodermann V, van Duijn J, van Pel M, et al. Mesenchymal stem cells reduce murine atherosclerosis development. Sci Rep 2015; 5(1): 15559.
[http://dx.doi.org/10.1038/srep15559] [PMID: 26490642]
[40]
Hong R, Wang Z, Sui A, et al. Gingival mesenchymal stem cells attenuate pro-inflammatory macrophages stimulated with oxidized low-density lipoprotein and modulate lipid metabolism. Arch Oral Biol 2019; 98: 92-8.
[http://dx.doi.org/10.1016/j.archoralbio.2018.11.007] [PMID: 30468993]
[41]
Yao G, Qi J, Li X, et al. Mesenchymal stem cell transplantation alleviated atherosclerosis in systemic lupus erythematosus through reducing MDSCs. Stem Cell Res Ther 2022; 13(1): 328.
[http://dx.doi.org/10.1186/s13287-022-03002-y] [PMID: 35850768]
[42]
Tilg H, Adolph TE, Dudek M, Knolle P. Non-alcoholic fatty liver disease: The interplay between metabolism, microbes and immunity. Nat Metab 2021; 3(12): 1596-607.
[http://dx.doi.org/10.1038/s42255-021-00501-9] [PMID: 34931080]
[43]
S S, Dahal S, Bastola S, Dayal S, Yau J, Ramamurthi A. Stem cell based approaches to modulate the matrix milieu in vascular disorders. Front Cardiovasc Med 2022; 9: 879977.
[http://dx.doi.org/10.3389/fcvm.2022.879977]
[44]
Li B, Cheng Y, Yu S, et al. Human umbilical cord-derived mesenchymal stem cell therapy ameliorates nonalcoholic fatty liver disease in obese type 2 diabetic mice. Stem Cells Int 2019; 2019: 1-12.
[http://dx.doi.org/10.1155/2019/8628027] [PMID: 31781248]
[45]
Ramasamy R, Fazekasova H, Lam EWF, Soeiro I, Lombardi G, Dazzi F. Mesenchymal stem cells inhibit dendritic cell differentiation and function by preventing entry into the cell cycle. Transplantation 2007; 83(1): 71-6.
[http://dx.doi.org/10.1097/01.tp.0000244572.24780.54] [PMID: 17220794]
[46]
Wang ZX, Wang CQ, Li XY, et al. Mesenchymal stem cells alleviate atherosclerosis by elevating number and function of CD4+ CD25+FOXP3+ regulatory T-cells and inhibiting macrophage foam cell formation. Mol Cell Biochem 2015; 400(1-2): 163-72.
[http://dx.doi.org/10.1007/s11010-014-2272-3] [PMID: 25389006]
[47]
Akiyama K, Chen C, Wang D, et al. Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis. Cell Stem Cell 2012; 10(5): 544-55.
[http://dx.doi.org/10.1016/j.stem.2012.03.007] [PMID: 22542159]
[48]
Li Q, Sun W, Wang X, Zhang K, Xi W, Gao P. Skin-derived mesenchymal stem cells alleviate atherosclerosis via modulating macrophage function. Stem Cells Transl Med 2015; 4(11): 1294-301.
[http://dx.doi.org/10.5966/sctm.2015-0020] [PMID: 26400926]
[49]
Takafuji Y, Hori M, Mizuno T, Harada-Shiba M. Humoral factors secreted from adipose tissue-derived mesenchymal stem cells ameliorate atherosclerosis in Ldlr−/− mice. Cardiovasc Res 2019; 115(6): 1041-51.
[http://dx.doi.org/10.1093/cvr/cvy271] [PMID: 30388208]
[50]
Wysoczynski M, Bolli R. A realistic appraisal of the use of embryonic stem cell-based therapies for cardiac repair. Eur Heart J 2020; 41(25): 2397-404.
[http://dx.doi.org/10.1093/eurheartj/ehz787] [PMID: 31778154]
[51]
Menasché P, Vanneaux V, Hagège A, et al. Transplantation of human embryonic stem cell–derived cardiovascular progenitors for severe ischemic left ventricular dysfunction. J Am Coll Cardiol 2018; 71(4): 429-38.
[http://dx.doi.org/10.1016/j.jacc.2017.11.047] [PMID: 29389360]
[52]
Yamanaka S. Pluripotent stem cell-based cell therapy-promise and challenges. Cell Stem Cell 2020; 27(4): 523-31.
[http://dx.doi.org/10.1016/j.stem.2020.09.014] [PMID: 33007237]
[53]
Sridharan D, Pracha N, Rana SJ, et al. Preclinical large animal porcine models for cardiac regeneration and its clinical translation: role of hipsc-derived cardiomyocytes. Cells 2023; 12(7): 1090.
[http://dx.doi.org/10.3390/cells12071090] [PMID: 37048163]
[54]
Menasché P. Skeletal myoblasts for cardiac repair: Act II? J Am Coll Cardiol 2008; 52(23): 1881-3.
[http://dx.doi.org/10.1016/j.jacc.2008.07.066] [PMID: 19038686]
[55]
Durrani S, Konoplyannikov M, Ashraf M, Haider KH. Skeletal myoblasts for cardiac repair. Regen Med 2010; 5(6): 919-32.
[http://dx.doi.org/10.2217/rme.10.65] [PMID: 21082891]
[56]
Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol 2008; 8(9): 726-36.
[http://dx.doi.org/10.1038/nri2395] [PMID: 19172693]
[57]
Golpanian S, Wolf A, Hatzistergos KE, Hare JM. Rebuilding the damaged heart: Mesenchymal stem cells, cell-based therapy, and engineered heart tissue. Physiol Rev 2016; 96(3): 1127-68.
[http://dx.doi.org/10.1152/physrev.00019.2015] [PMID: 27335447]
[58]
Hare JM, DiFede DL, Rieger AC, et al. Randomized comparison of allogeneic versus autologous mesenchymal stem cells for nonischemic dilated cardiomyopathy. J Am Coll Cardiol 2017; 69(5): 526-37.
[http://dx.doi.org/10.1016/j.jacc.2016.11.009] [PMID: 27856208]
[59]
Kawamoto A, Iwasaki H, Kusano K, et al. CD34-positive cells exhibit increased potency and safety for therapeutic neovascularization after myocardial infarction compared with total mononuclear cells. Circulation 2006; 114(20): 2163-9.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.106.644518] [PMID: 17075009]
[60]
Henry TD, Losordo DW, Traverse JH, et al. Autologous CD34+ cell therapy improves exercise capacity, angina frequency and reduces mortality in no-option refractory angina: A patient-level pooled analysis of randomized double-blinded trials. Eur Heart J 2018; 39(23): 2208-16.
[http://dx.doi.org/10.1093/eurheartj/ehx764] [PMID: 29315376]
[61]
Beltrami AP, Urbanek K, Kajstura J, et al. Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med 2001; 344(23): 1750-7.
[http://dx.doi.org/10.1056/NEJM200106073442303] [PMID: 11396441]
[62]
Bolli R, Mitrani RD, Hare JM, et al. A Phase II study of autologous mesenchymal stromal cells and c-kit positive cardiac cells, alone or in combination, in patients with ischaemic heart failure: The CCTRN CONCERT-HF trial. Eur J Heart Fail 2021; 23(4): 661-74.
[http://dx.doi.org/10.1002/ejhf.2178] [PMID: 33811444]
[63]
Malliaras K, Makkar RR, Smith RR, et al. Intracoronary cardiosphere-derived cells after myocardial infarction: Evidence of therapeutic regeneration in the final 1-year results of the CADUCEUS trial (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction). J Am Coll Cardiol 2014; 63(2): 110-22.
[http://dx.doi.org/10.1016/j.jacc.2013.08.724] [PMID: 24036024]
[64]
Makkar RR, Kereiakes DJ, Aguirre F, et al. Intracoronary ALLogeneic heart stem cells to achieve myocardial regeneration (ALLSTAR): A randomized, placebo-controlled, double-blinded trial. Eur Heart J 2020; 41(36): 3451-8.
[http://dx.doi.org/10.1093/eurheartj/ehaa541] [PMID: 32749459]
[65]
Henry TD, Schaer GL, Demaria A, et al. The ixCELL-DCM trial: Rationale and design. Cell Transplant 2016; 25(9): 1689-99.
[http://dx.doi.org/10.3727/096368916X691295] [PMID: 27009022]

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