Abstract
Bone marrow-derived mesenchymal stem cells are one of the most extensively characterized cell types in vitro as well in the experimental animal models. During the last decade, MSC-based cell therapy has progressed to phase-III clinical trials for the treatment of patients with heart failure. Although the earlier phase trials provide strong evidence to support the safety of MSCs-based cell therapy, the primary end points set forth for these studies have been only marginally achieved or at least not up to the anticipated levels of achievement. The minimal success in terms of their efficacy has been ascribed to a plethora of factors that encompass the quality of the cell preparation to the method of cell delivery as well as patient-related factors and the assessment methods used for the study end points. Our book chapter provides a brief description of these factors in general and a focussed analysis of published data from phase-II clinical trials to see how the route of cell delivery after myocardial infarction episode has impacted the outcome of these studies.
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Abbreviations
- 3D:
-
3-dimentsional
- AHA:
-
American Heart Association
- AMI:
-
Acute myocardial infarction
- BM:
-
Bone marrow
- BMSCs:
-
Bone marrow stem cells
- CABG:
-
Coronary artery bypass grafting
- CDCs:
-
Cardiosphere-derived cells
- CSCs:
-
Cardiac stem cells
- FDG:
-
Flourodeoxyglucose
- GFP:
-
Green fluorescence protein
- HLHS:
-
Hypoplastic left heart syndrome
- I/C:
-
Intracoronary
- I/M:
-
Intramyocardial
- I/V:
-
Intravenous
- ISCT:
-
International Society for Stem Cell Therapy
- LV:
-
Left ventricle
- LVAD:
-
Left ventricular assist device
- LVEF:
-
Left ventricular ejection fraction
- LVESV:
-
Left ventricular end-systolic volume
- MACE:
-
Major adverse cardiac events
- MI:
-
Myocardial infarction
- MSCs:
-
Mesenchymal stem cells
- PCI:
-
Percutaneous intervention
- PET:
-
Positron emission tomography
- PTCA:
-
Percutaneous transluminal angiography
- SPECT:
-
Single-photon emission computed tomography
- STEMI:
-
ST-elevation myocardial infarction
- TENDO:
-
Transendocardial
- TEPI:
-
Transepicardial
- VEGF:
-
Vascular endothelial growth factor
References
Abd Emami B, Mahmoudi E, Shokrgozar MA et al (2018) Mechanical and chemical predifferentiation of mesenchymal stem cells into cardiomyocytes and their effectiveness on acute myocardial infarction. Artif Org 42:E114–E126. https://doi.org/10.1111/aor.13091
Afzal MR, Haider HK, Idris NM (2007) Preconditioning promotes survival and proliferation of mesenchymal stem cells in the infarcted rat heart via activation of NF-κB downstream of PI3K/Akt signaling. Circulation 116:II_68
Aguero J, Lobo Gonzalez M, Ishikawa K (2017) Route TESI. Circ Res 120(7):1055–1056. https://doi.org/10.1161/circresaha.117.310701
Ali-Hasan-Al-Saegh S, Mirhosseini SJ, Lotfaliani MR et al (2015) Transplantation of bone marrow stem cells during cardiac surgery. Asian Cardiovasc Thorac Ann 23(3):363–374. https://doi.org/10.1177/0218492314553251
Anastasiadis K, Antonitsis P, Argiriadou H et al (2011) Hybrid approach of ventricular assist device and autologous bone marrow stem cells implantation in end-stage ischemic heart failure enhances myocardial reperfusion. J Transl Med 9:12. https://doi.org/10.1186/1479-5876-9-12
Antonitsis P, Anastasiadis K, Koliakos G et al (2012) Intramyocardial implantation of autologous bone marrow-derived stem cells combined with coronary artery bypass grafting in patients with ischemic cardiomyopathy: a pilot study. Hippokratia 16(4):366–370
Barbash I, Chouraqui P, Baron J et al (2003) Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium. Circulation 108(7):863–868. https://doi.org/10.1161/01.cir.0000084828.50310.6a
Bartolucci J, Verdugo F, González P et al (2017) Safety and efficacy of the intravenous infusion of umbilical cord mesenchymal stem cells in patients with heart failure. Circ Res 121(10):1192–1204. https://doi.org/10.1161/circresaha.117.310712
Bartunek J, Behfar A, Dolatabadi D et al (2013) Cardiopoietic stem cell therapy in heart failure: the C-CURE (Cardiopoietic stem Cell therapy in heart failURE) multicenter randomized trial with lineage-specified biologics [published correction appears in J Am Coll Cardiol 62(25):2457-8]. J Am Coll Cardiol 61(23):2329–2338. https://doi.org/10.1016/j.jacc.2013.02.071
Bolli R, Chugh AR, Damario D et al (2011) Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet 378(9806):1847–1857. https://doi.org/10.1016/S0140-6736(11)61590-0
Butler J, Epstein SE, Greene SJ et al (2017) Intravenous allogeneic mesenchymal stem cells for nonischemic cardiomyopathy: safety and efficacy results of a phase ii—a randomized trial. Circ Res 120(2):332–340. https://doi.org/10.1161/CIRCRESAHA.116.309717
Chakravarty T, Makkar RR, Ascheim DD et al (2017) ALLogeneic Heart STem Cells to Achieve Myocardial Regeneration (ALLSTAR) trial: rationale and design. Cell Transplant 26(2):205–214. https://doi.org/10.3727/096368916X692933
Chen Y, Li C, Li C 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 e013784:9. https://doi.org/10.1161/JAHA.119.013784
Chin S-P, Poey AC, Wong C-Y et al (2011) Intramyocardial and intracoronary autologous bone marrow-derived mesenchymal stromal cell treatment in chronic severe dilated cardiomyopathy. Cytotherapy 13:814–821. https://doi.org/10.3109/14653249.2011.574118
Choudhury T, Mozid A, Hamshere S et al (2017) An exploratory randomized control study of combination cytokine and adult autologous bone marrow progenitor cell administration in patients with ischaemic cardiomyopathy: the REGENERATE-IHD clinical trial. Eur J Heart Fail 19:138–147. https://doi.org/10.1002/ejhf.676
Chullikana A, Majumdar AS, Gottipamula S et al (2015) Randomized, double-blind, phase I/II study of intravenous allogeneic mesenchymal stromal cells in acute myocardial infarction. Cytotherapy 17(3):250–261. https://doi.org/10.1016/j.jcyt.2014.10.009
Coletta JE, Rosenthal N, Costa MA (2008) Cardiac mapping and stem cell delivery for thr damaged myocardium. Expert Rev Cardiovasc 6(9):1181–1190. https://doi.org/10.1586/14779072.6.9.1181
Delewi R, Hirsch A, Tijssen JG et al (2013) Impact of intracoronary bone marrow cell therapy on left ventricular function in the setting of ST-segment elevation myocardial infarction: a collaborative meta-analysis. Eur Heart J 35(15):989–998. https://doi.org/10.1093/eurheartj/eht372
Dib N, Haider KH, Varner S et al (2010) Cell therapy for cardiovascular disease: a comparison of methods of delivery. J Cardiovasc Transl Res 4(2):177–181. https://doi.org/10.1007/s12265-010-9253-z
Dominici M, Le Blanc K, Mueller I et al (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8(4):315–317. https://doi.org/10.1080/14653240600855905
Donndorf P, Kundt G, Kaminski A, Yerebakan C, Liebold A, Steinhoff G, Glass A (2011) Intramyocardial bone marrow stem cell transplantation during coronary artery bypass surgery: a meta-analysis. J Thorac Cardiovasc Surg 42(4):911–920. https://doi.org/10.1016/j.jtcvs.2010.12.013.
Donndorf P, Kaminski A, Tiedemann G (2012) Validating intramyocardial bone marrow stem cell therapy in combination with coronary artery bypass grafting, the PERFECT phase III randomized multicenter trial: study protocol for a randomized controlled trial. Trials 13:99. https://doi.org/10.1186/1745-6215-13-99
Durrani S, Konoplyannikov M, Ashraf M, Haider KH (2010) Skeletal myoblasts for cardiac repair. Regen Med 5(6):919–932. https://doi.org/10.2217/rme.10.65
Durrani S, Haider KH, Ahmed R (2012) Cytoprotective and proangiogenic activity of ex-vivo netrin-1 transgene overexpression protects the heart against ischemia/reperfusion injury. Stem Cells Dev 21(10):1769–1778. https://doi.org/10.1089/scd.2011.0475
Elmadbouh I, Haider H, Ashraf M (2011) Preconditioning of human skeletal myoblast with stromal cell-derived factor-12 promotes cytoprotective effects against oxidative and anoxic stress. Int J Stem Cells 4(1):50–60. https://doi.org/10.15283/ijsc.2011.4.1.50
Fan M, Huang Y, Chen Z et al (2019) Correction to: Efficacy of mesenchymal stem cell therapy in systolic heart failure: a systematic review and meta-analysis. Stem Cell Res Ther 10(1). https://doi.org/10.1186/s13287-019-1329-3
Fernández-Avilés F, Sanz-Ruiz R, Bogaert J et al (2018) Safety and efficacy of intracoronary infusion of allogeneic human cardiac stem cells in patients with ST-segment elevation myocardial infarction and left ventricular dysfunction. Circ Res 123(5):579–589. https://doi.org/10.1161/circresaha.118.312823
Freyman T, Polin G, Osman H et al (2006) A quantitative, randomized study evaluating three methods of mesenchymal stem cell delivery following myocardial infarction. Eur Heart J 27(9):1114–1122. https://doi.org/10.1093/eurheartj/ehi818
Fukushima S, Varela-Carver A, Coppen SR et al (2007) Direct intramyocardial but not intracoronary injection of bone marrow cells induces ventricular arrhythmias in a rat chronic ischemic heart failure model. Circulation 115(17):2254–2261. https://doi.org/10.1161/CIRCULATIONAHA.106.662577
Gao LR, Chen Y, Zhang NK et al (2015) Intracoronary infusion of Wharton’s jelly-derived mesenchymal stem cells in acute myocardial infarction: double-blind, randomized controlled trial. BMC Med 13:162. https://doi.org/10.1186/s12916-015-0399-z
Gathier WA, Ginkel DJ, vander Naald M et al (2018) Retrograde coronary venous infusion as a delivery strategy in regenerative cardiac therapy: an overview of preclinical and clinical data. J Cardiovasc Transl Res 11(3):173–181. https://doi.org/10.1007/s12265-018-9785-1
Gaudiello E, Melly L, Cerino G et al (2017) Scaffold composition determines the angiogenic outcome of cell-based vascular endothelial growth factor expression by modulating its microenvironmental distribution. Adv Healthc Mater 6(24). https://doi.org/10.1002/adhm.201700600
Grøgaard H, Sigurjonsson O, Brekke M et al (2007) Cardiac accumulation of bone marrow mononuclear progenitor cells after intracoronary or intravenous injection in pigs subjected to acute myocardial infarction with subsequent reperfusion. Cardiovas Revasc Med 8(1):21–27. https://doi.org/10.1016/j.carrev.2006.09.001
Grossman PM, Han Z, Palasis M et al (2002) Incomplete retention after direct myocardial injection. Catheter Cardiovasc Interv 55:392–397. https://doi.org/10.1002/ccd.10136.
Guijarro D, Lebrin M, Lairez O et al (2016) Intramyocardial transplantation of mesenchymal stromal cells for chronic myocardial ischemia and impaired left ventricular function: results of the MESAMI 1 pilot trial. Int J Cardiol 209:258–265. https://doi.org/10.1016/j.ijcard.2016.02.016
Guo R, Morimatsu M, Feng T (2020) Stem cell-derived cell sheet transplantation for heart tissue repair in myocardial infarction. Stem Cell Res Ther 11(1):19. https://doi.org/10.1186/s13287-019-1536-y
Gyöngyösi M, Haller PM, Blake DJ et al (2018) Meta-analysis of cell therapy studies in heart failure and acute myocardial infarction. Circ Res 123:301–308. https://doi.org/10.1161/CIRCRESAHA.117.311302
Haack-Sørensen M, Friis T, Mathiasen AB et al (2013) Direct intramyocardial mesenchymal stromal cell injections in patients with severe refractory angina: one-year follow-up. Cell Transplant 22:521–528. https://doi.org/10.3727/096368912X636830
Haider HK (2018) Bone marrow cell therapy and cardiac reparability: better cell characterization will enhance clinical success. Regen Med 13(4):457–475. https://doi.org/10.2217/rme-2017-0134
Haider HK, Aramini B (2020) Mircrining the injured heart with stem cell-derived exosomes: an emerging strategy of cell-free therapy. Stem Cell Res Ther 11(1):23. https://doi.org/10.1186/s13287-019-1548-7.
Haider HK, Ashraf M (2005) Bone marrow cell transplantation in clinical perspective. J Mol Cell Cardiol 38:225–235. https://doi.org/10.1016/j.yjmcc.2004.12.005
Haider HK, Ashraf M (2008) Strategies to promote donor cell survival: combining preconditioning approach with stem cell transplantation. J Mol Cell Cardiol 45(4):554–566. https://doi.org/10.1016/j.yjmcc.2008.05.004
Haider HK, Ashraf M (2010) Preconditioning and stem cell survival. J Cardiovasc Transl Res 3(2):89–102. https://doi.org/10.1007/s12265-009-9161-2.
Haider HK, Lei Y, Ashraf M (2008a) MyoCell, a cell-based, autologous skeletal myoblast therapy for the treatment of cardiovascular diseases. Curr Opin Mol Ther 10(6):611–621
Haider HK, Elmadbouh I, Jean-Baptiste M (2008b) Nonviral vector gene modification of stem cells for myocardial repair. Mol Med 14(1–2):79–86. https://doi.org/10.2119/2007-00092.haider
Haider HK, Jiang S, Niagara MI et al (2008c) IGF-I over expressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-1α/CXCR4 signaling to promote myocardial repair. Circ Res 103:1300–1308
Haider H, Lee Y, Jiang S (2010) Phosphodiesterase inhibition with tadalafil provides longer and sustained protection of stem cells. Am J Phys Heart Circ Phys 299(5):H1395–H1404. https://doi.org/10.1152/ajpheart.00437.2010
Halkos M, Zhao Z, Kerendi F et al (2008) Intravenous infusion of mesenchymal stem cells enhances regional perfusion and improves ventricular function in a porcine model of myocardial infarction. Basic Res Cardiol 103(6):525–536. https://doi.org/10.1007/s00395-008-0741-0
Hamano K, Nishida M, Hirata K et al (2001) Local implantation of autologous bone marrow cells for therapeutic angiogenesis in patients with ischemic heart disease: clinical trial and preliminary results. Jpn Circ J 65(9):845–847. https://doi.org/10.1253/jcj.65.845.
Hamshere S, Arnous S, Choudhury T et al (2015) Randomized trial of combination cytokine and adult autologous bone marrow progenitor cell administration in patients with non-ischaemic dilated cardiomyopathy: the REGENERATE-DCM clinical trial. Eur Heart J 36(44):3061–3069. https://doi.org/10.1093/eurheartj/ehv390
Hare JM, Traverse JH, Henry TD et al (2009) A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol 54(24):2277–2286. https://doi.org/10.1016/j.jacc.2009.06.055
Hare JM, Fishman JE, Gerstenblith G et al (2012) 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 308(22):2369–2379. https://doi.org/10.1001/jama.2012.25321
Hare JM, DiFede DL, Rieger AC et al (2017) Randomized comparison of allogeneic versus autologous mesenchymal stem cells for nonischemic dilated cardiomyopathy: POSEIDON-DCM trial. J Am Coll Cardiol 69(5):526–537. https://doi.org/10.1016/j.jacc.2016.11.009
Heldman AW, DiFede DL, Fishman JE et al (2014) Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial. JAMA 311(1):62–73. https://doi.org/10.1001/jama.2013.282909
Hendrikx M, Hensen K, Clijsters C et al (2006) Recovery of regional but not global contractile function by the direct intramyocardial autologous bone marrow transplantation: results from a randomized controlled clinical trial. Circulation 114:I101–I107. https://doi.org/10.1161/CIRCULATIONAHA.105.000505
Hofmann M, Wollert K, Meyer G et al (2005) Monitoring of bone marrow cell homing into the infarcted human myocardium. Circulation 111(17):2198–2202. https://doi.org/10.1161/01.cir.0000163546.27639.aa
Hou D, Youssef EA, Brinton TJ et al (2005) Radiolabeled cell distribution after intramyocardial, intracoronary, and interstitial retrograde coronary venous delivery: implications for current clinical trials. Circulation 112(9 Suppl):I150–I156. https://doi.org/10.1161/CIRCULATIONAHA.104.526749
Huang P, Wang L, Li Q et al (2019) Combinatorial treatment of acute myocardial infarction using stem cells and their derived exosomes resulted in improved heart performance. Stem Cell Res Ther 10:300. https://doi.org/10.1186/s13287-019-1353-3
Hudson W, Collins MC, deFreitas D et al (2007) Beating and arrested intramyocardial injections are associated with significant mechanical loss: implications for cardiac cell transplantation. J Surg Res 142:263–267. https://doi.org/10.1016/j.jss.2007.03.021
Ishigami S, Ohtsuki S, Tarui S et al (2015) Intracoronary autologous cardiac progenitor cell transfer in patients with hypoplastic left heart syndrome: the TICAP prospective phase 1 controlled trial. Circ Res 116(4):653–664. https://doi.org/10.1161/CIRCRESAHA.116.304671
Jayaraj JC, Davatyan K, Subramanian S, Priya J (2019) Epidemiology of myocardial infarction. myocardial infarction. Cereus 11(9):e5585. https://doi.org/10.7759/cureus.5585
Joanne P, Kitsara M, Boitard SE et al (2016) Nanofibrous clinical-grade collagen scaffolds seeded with human cardiomyocytes induces cardiac remodeling in dilated cardiomyopathy. Biomaterials 80:157–168. https://doi.org/10.1016/j.biomaterials.2015.11.035
Joseph J (2014) Needling the heart to rejuvenate: the promise of intramyocardial injection of bone marrow stem cells. Editorial commentary. J Heart Lung Transplant 33(6):565–566. https://doi.org/10.1016/j.healun.2014.02.029
Kabat M, Bobkov I, Kumar S et al (2020) Trends in mesenchymal stem cell clinical trials 2004-2018: is efficacy optimal in a narrow dose range? Stem Cells Transl Med 9:17–27. https://doi.org/10.1002/sctm.19-0202
Kanelidis AJ, Premer C, Lopez J et al (2017) Route of delivery modulates the efficacy of mesenchymal stem cell therapy for myocardial infarction: a meta-analysis of preclinical studies and clinical trials. Circ Res 120(7):1139–1150. https://doi.org/10.1161/CIRCRESAHA.116.309819
Karantalis V, DiFede DL, Gerstenblith G et al (2014) Autologous mesenchymal stem cells produce concordant improvements in regional function, tissue perfusion, and fibrotic burden when administered to patients undergoing coronary artery bypass grafting: the prospective randomized study of mesenchymal stem cell therapy in patients undergoing cardiac surgery (Prometheus) trial. Circ Res 114(8):1302–1310. https://doi.org/10.1161/CIRCRESAHA.114.303180
Khan K, Gasbarrino K, Mahmoud I et al (2018) Bioactive scaffolds in stem-cell-based therapies for cardiac repair: protocol for a meta-analysis of randomized controlled preclinical trials in animal myocardial infarction models. Syst Rev 7(1):225. https://doi.org/10.1186/s13643-018-0845-z.
Kim HW, Haider KH, Jiang S et al (2009) Ischemic preconditioning augments survival of stem cells via miR-107 and miR-210 expression. J Biol Chem 284:33161–33168
Kim HW, Jiang S, Ashraf M (2012a) Stem cell-based delivery of hypoxamir-210 to the infarcted heart: implications on stem cell survival and preservation of infarcted heart function. J Mol Med 90(9):997–1010. https://doi.org/10.1007/s00109-012-0920-1
Kim HW, Mallick F, Durrani S (2012b) Concomitant activation of miR-107/PDCD10 and hypoxamir-210/Casp8ap2 and their role in cytoprotection during ischemic preconditioning of stem cells. Antioxid Redox Signal 17(8):1053–1065. https://doi.org/10.1089/ars.2012.4518
Kim J-H, Han J, Seo D et al (2020) Characterization of mesenchymal stem cells derived from patients with cerebellar ataxia: downregulation of the anti-inflammatory secretome profile. Cell 9(1):212. https://doi.org/10.3390/cells9010212
Kretlow JD, Klouda L, Mikos AG (2007) Injectable matrices and scaffolds for drug delivery in tissue engineering. Adv Drug Deliv Rev 59(4–5):263–273. https://doi.org/10.1016/j.addr.2007.03.013.
Kurdi M, Chidiac R, Hoemann C (2010) Hydrogels as a platform for stem cell delivery to the heart. Congest Heart Fail 16(3):132–135. https://doi.org/10.1111/j.1751-7133.2010.00145.x
Kurtz A (2008) Mesenchymal stem cell delivery routes and fate. Int J Stem Cells 1(1):1–7. https://doi.org/10.15283/ijsc.2008.1.1.1
Lalu MM, Mazzarello S, Zlepnig J 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(12):857–866. https://doi.org/10.1002/sctm.18-0120
Le Visage C, Gournay O, Benguirat N et al (2012) Mesenchymal stem cell delivery into rat infarcted myocardium using a porous polysaccharide-based scaffold: a quantitative comparison with endocardial injection. Tissue Eng Part A 18(1–2):35–44. https://doi.org/10.1089/ten.tea.2011.0053
Lee J-W, Lee S-H, Youn Y-J et al (2014) A randomized, open-label, multicenter trial for the safety and efficacy of adult mesenchymal stem cells after acute myocardial infarction. J Korean Med Sci 29(1):23–31. https://doi.org/10.3346/jkms.2014.29.1.23
Li Y, Sheng Z, Yang Y (2011) Dual-modal tracking of transplanted mesenchymal stem cells after myocardial infarction. Int J Nanomedicine 6:815
Lian W-S, Cheng WT-K, Cheng C-C et al (2011) In vivo therapy of myocardial infarction with mesenchymal stem cells modified with prostaglandin I synthase gene improves cardiac performance in mice. Life Sci 88(9–10):455–464
Lim M, Wang W, Liang L et al (2018) Intravenous injection of allogeneic umbilical cord-derived multipotent mesenchymal stromal cells reduces the infarct area and ameliorates cardiac function in a porcine model of acute myocardial infarction. Stem Cell Res Ther 9(1). https://doi.org/10.1186/s13287-018-0888-z
Lipinski MJ, Biondi-Zoccai GG, Abbate A et al (2007) Impact of intracoronary cell therapy on left ventricular function in the setting of acute myocardial infarction: a collaborative systematic review and meta-analysis of controlled clinical trials. J Am Coll Cardiol 50(18):1761–1767. https://doi.org/10.1016/j.jacc.2007.07.041
Lu G, Haider HK, Jiang S (2009a) Sca-1+ stem cell survival and engraftment in the infarcted heart: dual role for preconditioning-induced connexin-43. Circulation 119(19):2587–2596
Lu G, Haider HK, Porollo A (2009b) Mitochondrial connexin-43 shares a common BH3 motif with BcL-2 family members to impart cytoprotection in preconditioned Sca-1(+) cells via regulation of cytochrome-c release. Circulation 120(issue: 18 supplement):2
Lu G, Shujia J, Haider HK (2011) Mitochondrial transgenic expression of connexin 43 confers cytoprotection to the stem cells and cardiomyocytes in ischemic myocardium. Circulation 124(issue: 21 supplement):A131
Lu G, Ashraf M, Haider K (2012a) Insulin-like growth factor-1 preconditioning accentuates intrinsic survival mechanism in stem cells to resist ischemic injury by orchestrating protein kinase Cα–Erk1/2 activation. Antioxid Redox Signal 16(3):217–227. https://doi.org/10.1089/ars.2011.4112
Lu G, Jiang S, Ashraf M (2012b) Mitochondria specific connexin-43 transgene expression protects stem cells in the ischemic heart via shifting the balance between Bak and Bcl-xL. Regen Med 7(3):323–334
Luo L, Tang J, Nishi K et al (2017) Fabrication of synthetic mesenchymal stem cells for the treatment of acute myocardial infarction in mice. Circ Res 120(11):1768–1775
Makkar RR, Price MJ, Lill M et al (2005) Intramyocardial injection of allogeneic bone marrow-derived mesenchymal stem cells without immunosuppression preserves cardiac function in a porcine model of myocardial infarction. J Cardiovas Pharmacol Therap 10(4):225–233
Makkar RR, Smith RR, Cheng K et al (2012) Intrcoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet 379(9819):895–904. https://doi.org/10.1016/S0140-6736(12)60195-0.
Mansour S, Roy D, Bouchard V et al (2011) One-year safety analysis of the COMPARE-AMI trial: comparison of intracoronary injection of CD133+ bone marrow stem cells to placebo in patients after acute myocardial infarction and left ventricular dysfunction. Bone Marrow Res 2011:1–6. https://doi.org/10.1155/2011/385124
Mathiasen AB, Qayyum AA, Jørgensen E et al (2015) 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 36(27):1744–1753. https://doi.org/10.1093/eurheartj/ehv136
Menasche P, Hagege AA, Scorsin M et al (2001) Myoblast transplantation for heart failure. Lancet 357(9252):279–280. https://doi.org/10.1016/S0140-6736(00)03617-5
Mewhort HE, Turnbull JD, Meijndert HC et al (2014) Epicardial infarct repair with basic fibroblast growth factor-enhanced CorMatrix-ECM biomaterial attenuates postischemic cardiac remodeling. J Thorac Cardiovasc Surg 147(5):1650–1659. https://doi.org/10.1016/j.jtcvs.2013.08.005
Mewhort HE, Turnbull JD, Satriano A (2016) Epicardial infarct repair with bioinductive extracellular matrix promotes vasculogenesis and myocardial recovery. J Heart Lung Transplant 35(5):661–670. https://doi.org/10.1016/j.healun.2016.01.012
Mitchell AJ, Sabondjian E, Sykes J (2010) Comparison of initial cell retention and clearance kinetics after subendocardial or subepicardial injections of endothelial progenitor cells in a canine myocardial infarction model. J Nucl Med 51:413–417. https://doi.org/10.2967/jnumed.109.069732
Mozid A, Yeo C, Arnous S et al (2014) Safety and feasibility of intramyocardial versus intracoronary delivery of autologous cell therapy in advanced heart failure: the REGENERATE-IHD pilot study. Regen Med 9(3):269–278. https://doi.org/10.2217/rme.14.3
Mykhaylichenko V, Kubyshkin A, Samarin S et al (2016) Experimental induction of reparative morphogenesis and adaptive reserves in the ischemic myocardium using multipotent mesenchymal bone marrow-derived stem cells. Pathophysiology 23(2):95–104
Nasseri BA, Ebell W, Dandel M (2014) Autologous CD133+ bone marrow cells and bypass grafting for regeneration of ischaemic myocardium: the Cardio133 trial. Eur Heart J 35(19):1263–1274. https://doi.org/10.1093/eurheartj/ehu007
O’Cearbhaill ED, Ng KS, Karp JM (2014) Emerging medical devices for minimally invasive cell therapy. Mayo Clin Proc 89(2):259–273. https://doi.org/10.1016/j.mayocp.2013.10.020
Pacelli S, Basu S, Whitlow J (2017) Strategies to develop endogenous stem cell-recruiting bioactive materials for tissue repair and regeneration. Adv Drug Deliv Rev 120:50–70. https://doi.org/10.1016/j.addr.2017.07.011
Pagani FD, DerSimonian H, Zawadzka A et al (2003) Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans. Histological analysis of cell survival and differentiation. J Am Coll Cardiol 41(5):879–888. https://doi.org/10.1016/s0735-1097(03)00081-0.
Pätilä T, Lehtinen M, Vento A et al (2014) Autologous bone marrow mononuclear cell transplantation in ischemic heart failure: a prospective, controlled, randomized, double-blind study of cell transplantation combined with coronary bypass. J Heart Lung Transplant 33(6):567–574. https://doi.org/10.1016/j.healun.2014.02.009
Péreza LM, de Lucasa B, Gálveza BG (2018) Unhealthy stem cells: when health conditions upset stem cell properties. Cell Physiol Biochem 46:1999–2016. https://doi.org/10.1159/000489440
Perin E, López J (2006) Methods of stem cell delivery in cardiac diseases. Nat Clin Prac Cardiovas Med 3(S1):S110–S113. https://doi.org/10.1038/ncpcardio0447
Perin EC, Dohmann HFR, Borojevic R et al (2003) Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation 107(18):2294–2302. https://doi.org/10.1161/01.CIR.0000070596.30552.8B
Picken A, Harriman J, Iftimia-Mander A et al (2020) A Monte Carlo framework for managing biological variability in manufacture of autologous cell therapy from mesenchymal stromal cells therapies. Cytotherapy 22(4):227–238. https://doi.org/10.1016/j.jcyt.2020.01.006
Pompilio G, Steinhoff G, Liebold A et al (2008) Direct minimally invasive intramyocardial injection of bone marrow-derived AC133+ stem cells in patients with refractory ischemia: preliminary results. Thoracic Cardiovasc Surg 56(2):71–76. https://doi.org/10.1055/s-2007-989351
Qiu F, Maehara A, El Khoury R et al (2016) Impact of intracoronary injection of CD133+ bone marrow stem cells on coronary atherosclerotic progression in patients with STEMI. Coron Artery Dis 27(1):5–12. https://doi.org/10.1097/mca.0000000000000302
Rahbarghazi R, Nassiri SM, Ahmadi SH et al (2014) Dynamic induction of pro-angiogenic milieu after transplantation of marrow-derived mesenchymal stem cells in experimental myocardial infarction. Int J Cardiol 173(3):453–466
Ramireddy A, Brodt CR, Mendizabal AM et al (2017) 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 6(5):1366–1372. https://doi.org/10.1002/sctm.16-0328.
Rodrigo SF, van Ramshorst J, Hoogslag JE et al (2013) Intramyocardial injection of autologous bone marrow-derived ex vivo expanded mesenchymal stem cells in acute myocardial infarction patients is feasible and safe up to 5 years of follow-up. J Cardiovasc Trans Res 6:816–825. https://doi.org/10.1007/s12265-013-9507-7
Schuleri KH, Amado LC, Boyle AJ et al (2008) Early improvement in cardiac tissue perfusion due to mesenchymal stem cells. Am J Physiol Heart Circ Physiol 294(5)
Shahid MS, Lasheen W, Haider HK (2016) Modest outcome of clinical trials with bone marrow cells for myocardial repair: is the autologous source of cells the prime culprit? J Thorac Dis 8(10):E1371–E1374. https://doi.org/10.21037/jtd.2016.10.37
Sheng CC, Zhou L, Hao J (2012) Current stem cell delivery methods for myocardial repair. Bio Med Res Int 2013:Article ID 547902. https://doi.org/10.1155/2013/547902
Sherman W, Martens TP, Viles-Gonzalez J et al (2006) Catheter-based delivery of cells to the heart. Nat Clin Pract Cardiovas Med 3:S57–S64. https://doi.org/10.1038/ncpcardio0446
Sim EK, Haider HK, Aziz S (2005) Myoblast transplantation on the beating heart. Int Surg 90(3):148–150
Stempien-Otero A, Helterline D, Plummer T et al (2015) Mechanisms of bone marrow-derived cell therapy in ischemic cardiomyopathy with left ventricular assist device bridge to transplant. J Am Coll Cardiol 65(14):1424–1434. https://doi.org/10.1016/j.jacc.2015.01.042
Stephanie MW, Sakiyama-Elbert SE (2019) Combining stem cells and biomaterial scaffolds for constructing tissues and cell delivery. Stem J 1(1):1–25
Strauer BE, Yousef M, Schannwell CM (2010) The acute and long-term effects of intracoronary stem cell transplantation in 191 patients with chronic heart failure: the STAR heart study. Eur J Heart Fail 12:721–729. https://doi.org/10.1093/eurjhf/hfq095
Streeter BW, Xue J, Xia Y et al (2019) Electrospun nanofiber-based patches for the delivery of cardiac progenitor cells. ACS Appl Mater Interfaces 11(20):18242–18253. https://doi.org/10.1021/acsami.9b04473
Suncion VY, Ghersin E, Fishman JE et al (2014) Does transendocardial injection of mesenchymal stem cells improve myocardial function locally or globally?: an analysis from the Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis (POSEIDON) randomized trial. Circ Res 114(8):1292–1301. https://doi.org/10.1161/CIRCRESAHA.114.302854
Svystonyuk DA, Mewhort HEM, Fedak PWM (2018) Using acellular bioactive extracellular matrix scaffolds to enhance endogenous cardiac repair. Front Cardiovasc Med 5(Article 35):1–10. https://doi.org/10.3389/fcvm.2018.00035
Takehara N, Nagata M, Ogata T, Nakamura T, Matoba S, Gojo S, Sawada T, Yaku H, Matsubara H (2012) The ALCADIA (Autologous Human Cardiac-derived Stem Cell To Treat Ischemic Cardiomyopathy) trial. AHA 2012; LBCT-20032
Teng C, Luo J, Chiu R (2006) Massive mechanical loss of microspheres with direct intramyocardial injection in the beating heart: implications for cellular cardiomyoplasty. J Thorac Cardiovasc Surg 132(3):628–632. https://doi.org/10.1016/j.jtcvs.2006.05.034
Tokita Y, Tang X, Li Q et al (2016) Repeated administrations of cardiac progenitor cells are markedly more effective than a single administration. Circ Res 119(5):635–651. https://doi.org/10.1161/circresaha.116.308937
Tse H-F, Kwong Y-L, Chan JKF (2003) Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet 361(9351):P47–P49. https://doi.org/10.1016/S0140-6736(03)12111-3.
Tsubokawa T, Yagi K, Nakanishi C et al (2010) Impact of anti-apoptotic and anti-oxidative effects of bone marrow mesenchymal stem cells with transient overexpression of heme oxygenase-1 on myocardial ischemia. Am J Physiol Heart Circ Physiol 298(5):H1320-9
Valina C, Pinkernell K, Song Y-H et al (2007) Intracoronary administration of autologous adipose tissue-derived stem cells improves left ventricular function, perfusion, and remodelling after acute myocardial infarction. Eur Heart J 28(21):2667–2677
Varghese J, Griffin M, Mosahebi A (2017) Systematic review of patient factors affecting adipose stem cell viability and function: implications for regenerative therapy. Stem Cell Res Ther 8:45. https://doi.org/10.1186/s13287-017-0483-8
Vasanthan V, Fatehi Hassanabad A, Pattar S et al (2020) Promoting cardiac regeneration and repair using acellular biomaterials. Front Bioeng Biotechnol 8:291. https://doi.org/10.3389/fbioe.2020.00291.
Virani SS, Alonso A, Benjamin EJ et al (2020) Heart disease and stroke statistics—2020 update a report from the AHA. Circulation 141:e1–e458. https://doi.org/10.1161/CIR.0000000000000757
Vrtovec B, Bolli R (2019) Potential strategies for clinical translation of repeated cell therapy. Circ Res 124(5):690–692. https://doi.org/10.1161/circresaha.118.314653
Vulliet PR, Greeley M, Halloran SM (2004) Intra-coronary arterial injection of mesenchymal stromal cells and microinfarction in dogs. Lancet 363(9411):783–784. https://doi.org/10.1016/S0140-6736(04)15695-X
Wang Y, Haider HK, Ahmad N et al (2006) Combining pharmacological mobilization with intramyocardial delivery of bone marrow cells over-expressing VEGF is more effective for cardiac repair. J Mol Cell Cardiol 40(5):736–745. https://doi.org/10.1016/j.yjmcc.2006.02.004.
Wang C-C, Chen C-H, Lin W et al (2008) Direct intramyocardial injection of mesenchymal stem cell sheet fragments improves cardiac functions after infarction. Cardiovasc Res 77:515–524. https://doi.org/10.1093/cvr/cvm046
Wang W, Jiang Q, Zhang H et al (2011) Intravenous administration of bone marrow mesenchymal stromal cells is safe for the lung in a chronic myocardial infarction model. Regen Med 6(2):179–190. https://doi.org/10.2217/rme.10.104
Wang P, Wang H, Ma K et al (2020) Novel cytokine-loaded PCL-PEG scaffold composites for spinal cord injury repair. RSC Adv 10:6306–6314. https://doi.org/10.1039/C9RA10385F
Wollert KC, Drexler H (2010) Cell therapy for the treatment of coronary heart disease: a critical appraisal. Nat Rev Cardiol 7:204–215. https://doi.org/10.1038/nrcardio.2010.1
Wysoczynki M, Khan A, Bolli R (2018) New paradigms in cell therapy: repeated dosing, intravenous delivery, immunomodulatory actions, and new cell types. Circ Res 123(2):138–158. https://doi.org/10.1161/circresaha.118.313251
Xu J, Xiong Y, Li Q et al (2019) Optimization of timing and times for administration of atorvastatin-pretreated mesenchymal stem cells in a preclinical model of acute myocardial infarction. Stem Cells Transl Med 8(10):1068–1083. https://doi.org/10.1002/sctm.19-0013
Yaniz-Galende E, Roux M, Nadaud S et al (2017) Fibrogenic potential of PW1/Peg3 expressing cardiac stem cells. J Am Coll Cardiol 70(6):728–741. https://doi.org/10.1016/j.jacc.2017.06.010
Yao Y, Huang J, Geng Y et al (2015) Paracrine action of mesenchymal stem cells revealed by single cell gene profiling in infarcted murine hearts. PLoS One 10(6)
Yau TM, Pagani FD, Mancini DM et al (2019) Intramyocardial injection of mesenchymal precursor cells and successful temporary weaning from left ventricular assist device support in patients with advanced heart failure: a randomized clinical trial. JAMA 321(12):1176–1186. https://doi.org/10.1001/jama.2019.2341
Zakharova L, Mastroeni D, Mutlu N (2010) Transplantation of cardiac progenitor cell sheet onto infarcted heart promotes cardiogenesis and improves function. Cardiovasc Res 87(1):40–49. https://doi.org/10.1093/cvr/cvq027
Zhang G-W, Gu T-X, Guan X-Y et al (2015) HGF and IGF-1 promote protective effects of allogeneic BMSC transplantation in rabbit model of acute myocardial infarction. Cell Prolif 48(6):661–670
Zhao Q, Sun Y, Xia L et al (2008) Randomized study of mononuclear bone marrow cell transplantation in patients with coronary surgery. Ann Thorac Surg 86(6):1833–1840. https://doi.org/10.1016/j.athoracsur.2008.08.068
Zhao X, Xu Y, Zhu Z (2015) Clinical observation of umbilical cord mesenchymal stem cell treatment of severe systolic heart failure. Genet Mol Res 14(2):3010–3017. https://doi.org/10.4238/2015.april.10.11
Zwetsloot PP, Végh AM, Jansen of Lorkeers SJ H et al (2016) Cardiac stem cell treatment in myocardial infarction: a systematic review and meta-analysis of preclinical studies. Circ Res 118(8):1223–1232. https://doi.org/10.1161/CIRCRESAHA.115.307676
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Kalou, Y.M.N., Hashemi, A.S.A., Joudeh, R.M., Aramini, B., Haider, K.H. (2021). Mesenchymal Stem Cell-Based Heart Cell Therapy: The Effect of Route of Cell Delivery in the Clinical Perspective. In: Haider, K.H. (eds) Stem cells: From Potential to Promise. Springer, Singapore. https://doi.org/10.1007/978-981-16-0301-3_6
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