Table 1 |.
Cardiac regenerative therapies in preclinical studies
| Therapeutic source | Animal model and age | Cohort (n) | Disease model | Delivery method | Cardiac function recovery versus control; assessment method | Comments | Ref. |
|---|---|---|---|---|---|---|---|
| Cardiac stem cells | |||||||
| Autologous CDCs (1 X 107) | • Pig • Adult | • C = 11 • T = 10 | • IHF • MI | • Intramyocardial • 4 weeks after MI | • LVEF improvement (~7%) at 8 weeks • Ventriculography | LacZ+ CDCs detected in the peri-infarct zone with the use of cardiac marker expression | 56 |
| Autologous KIT+ CSCs (5 X 105) | • Pig • 8–10 weeks | • C = 10 • T = 11 | • IHF • IR 90 min | • Intracoronary • 3–4 months after IR | • LVEF improvement (8–10%) at 8 weeks • Echocardiography | EGFP-labelled CSC- derived cells detected in the infarct zone with the use of cardiac marker expression | 57 |
| Pluripotent stem cells | |||||||
| Human ESC- CMs (~1 X 109) | • Macaque • 5–14 years | • C = 2 • T=4 | • IHF • IR 90 min | • Intramyocardial • 14 days after MI | • No significant change in LVEF • Echocardiography | • Proof-of-principle study • GFP-labelled human ESC-CMs detected in the peri-infarct zone • Electromechanical integration with host myocardium • All animals receiving cell transplants had ventricular arrhythmias | 69 |
| Allogeneic iPSC-CMs (4 X 108) | • Macaque • 4–5 years | • C = 5 • T = 5 | • IHF • MI | • Intramyocardial • 14 days after MI | • LVEF improvement (~10%) at 12 weeks • CT imaging | • GFP-labelled iPSC-CMs detected in the peri- infarct zone • Electromechanical integration with host myocardium • All animals receiving cell transplants had ventricular arrhythmias | 74 |
| Secretory factors | |||||||
| • NRG1-MPs • FGF1-MPs | • Pig • 12–24 months | • C = 6 • T (NRG1-MPs) = 5 • T (FGF1-MPs) = 6 | • IHF • IR 120 min | • Intramyocardial • 1 week after MI | • LVFS improvement (~9%) at 3 months • Echocardiography | • Increase in vascularization with NRG1-MP and FGF1-MP treatment • Reduced fibrosis with NRG1-MP treatment | 91 |
| • miR-199a-3p • miR-590–3p | • Mouse • 2 months | • C = 13 • T (miR-199a-3p) = 20 • T (miR-590–3p) = 13 | • IHF • MI | • Intramyocardial • After coronary ligation (with cationic lipid formulations) | • LVEF improvement (10–20%) at 8 weeks • Echocardiography | Increased numbers in the peri-infarct zone of CMs positive for the DNA synthesis marker EdU | 97 |
| Human CDC-derived exosomes (~16.5 X 1011) | • Pig • Adult | • C = 6 • T = 6 | • IHF • MI | • Intramyocardial • 4 weeks after MI | • LVEF improvement (~5%) at 1 month • MRI | • Reduced scar size • Increased numbers in the peri-infarct zone of CMs positive for the cell cycle active phase marker Ki67 | 109 |
| Direct cardiacreprogramming | |||||||
| Retroviral GMT | • Mouse • 2 months | • C = 9 • T = 9 | • IHF • MI | • Intramyocardial • After coronary ligation | • LVEF improvement (~10%) at 12 weeks • MRI | • Reduced scar size • Fibroblast lineage- traced cells (Fsp1-Cre or Postn-Cre) expressing cardiac markers in the peri-infarct zone | 135 |
| Retroviral GHMT | • Mouse • 8–10 weeks | • C = 9 • T = 10 | • IHF • MI | • Intramyocardial • After coronary ligation | • LVEF improvement (~25%) at 12 weeks • MRI | • Reduced scar size • Fibroblast lineage- traced cells (Tcf21 -Cre) expressing cardiac markers in the peri-infarct zone | 18 |
| Stimulation of endogenous cardiac repair | |||||||
| Agrin | • Mouse • 12 weeks | • C = 7 • T = 8 | • IHF • MI | • Intramyocardial • After coronary ligation | • LVEF improvement (~10%) at 5 weeks • Echocardiography | • Reduced scar size • Increased numbers in the peri-infarct zone of CMs positive for the proliferation markers Ki67, BrdU, and AURKB | 166 |
| Systemic | • Mouse | • C = 9 | • IHF | • Gradual hypoxia | • LVEF improvement | • Reduced scar size | 168 |
| exposure to hypoxia | • 2 months | • T = 9 | • MI | induction reaching 7% O2 level for 2 weeks • 1 week after MI | (~20%) at ~6 weeks • Echocardiography | • Increased numbers of BrdU+ CMs, PHH3+ CMs, and AURKB+ CMs, mainly in the MI remote zone | |
AURKB, aurora kinase B; BrdU, 5-bromodeoxyuridine; C, control; CDC, cardiosphere-derived cell; CM, cardiomyocyte; CSC, cardiac stem cell; EdU, 5-ethynyl-2’-deoxyuridine; EGFP, enhanced green fluorescent protein; ESC, embryonic stem cell; FGF1, fibroblast growth factor 1; GFP, green fluorescent protein; GMT, Gata4, Mef2c, and Tbx5; GHMT, Gata4, Hand2, Mef2c, and Tbx5; IHF, ischaemic heart failure; iPSC, induced pluripotent stem cell; IR, ischaemia-reperfusion; KIT, mast/stem cell growth factor receptor KIT; LVEF, left ventricular ejection fraction; LVFS, left ventricular fractional shortening; MI, myocardial infarction; MP, microparticle; NRG1, neuregulin 1; PHH3, phosphohistone H3; T, treatment.