Copyright ©The Author(s) 2022.
World J Stem Cells. Jan 26, 2022; 14(1): 1-40
Published online Jan 26, 2022. doi: 10.4252/wjsc.v14.i1.1
Table 1 Main outcomes of the studies investigated the impact of nanotechnology in cardiac stem cell-based studies
Nanotechnology field
Types of nanoparticles
Type of cardiac disease/stem cells
Type of research
Tissue engineering Semi-crystalline PLLA nanostructured membranes among several PLGA membranesNon-diseased/primary CMs In vitro: electrospun matrices were used as scaffolds for generating cardiac tissue constructsNanostructured non-woven PLLA scaffolds provide flexibility and guidance for CMs growth and can be successfully applied to obtain structurally and functionally competent cardiac tissue constructs. [201]
Tissue engineeringECM-mimicking nanofibrous PLLA scaffolds with porous structure (porous NF PLLA) of high interconnection for cardiac tissue formationNon-diseased/mouse ESCsIn vitro: CPCs with porous NF PLLAIn vitro: porous NF PLLA scaffolds facilitate cell attachment, extension, and differentiation. [202]
In vivo: male athymic nude mice
In vivo: subcutaneous implantation of cell/scaffold supports survival of grafted cells and differentiation to CMs, SMCs, ECs lineages.
Tissue engineering/therapeutic Biodegradable ANFMI/hiPSCs-CMsIn vitro: hiPSCs (253G1)In vitro: multilayered, elongated, organized CMs at high density along ANF, with up regulation of genes of sarcomere structures (ACTN2, TNNT2, TNNI3), cardiac maturation (MYH7), ventricular structures (MYL2, HAND2).[203]
In vivo: nude rat
In vivo: CTLCs improve MI functionally due to transplantation of organized functional CMs.
Tissue engineering Electroactive Au-Lap NPs loaded myocardial ECMNon diseased/Resident CSCsIn vitro: rat CMs from 2-d old neonatal ratsCombination of electrically active nano-formulations and biologically active ECM boost the expression of cardiac-specific proteins (SAC, cTnl, Cx43).[204]
Therapeutic Self-assembling peptide nanofibers tethered with insulin-like growth factor-1 (NF-IGF-1)MI/CPCsIn vitro: clonogenic CPCsIn vitro: NF-IGF-1 promote CPCs division (↑BrdU) and protect them from death signal (↓TdT). [207]
In vivo: CPCs-NF-IGF-1 enhance postinfarction ventricular remodeling, attenuate chamber dilation, and improve cardiac performance.
In vivo: female Fischer 344 rats
Therapeutic Transplantation of self-assembling nanopeptides: Cell-PM complexMI/cSCA-1+ cardiac progenitors Other stem cells BM, SM, AMCIn vivo: Wild-type mice (C57Bl/6J); Adult GFP transgenic micecSCA-1/PM attenuates ventricular enlargement, restore cardiac function, with high capillary density (↑vWF) and conductive vessels (↑αSMA, ↑VEGF). [208]
↓TUNEL+ CMs in the infarct area of cSCA-1/PM.
Therapeutic CMMP contained control-released stem cell factors in its polymeric core and cloaked with hCSC membrane fragments on the surfaceMI/Human CSCsIn situ: characterizationIn situ: CMMPs express hCSC surface markers.[209]
In vitro: NRCM
In vivo: male SCID Beige mice
In vitro: CMMPs promote NRCM contractility and proliferation.
In vivo: CMMPs preserve viable myocardium, augment cardiac functions, with safety profile.
Therapeutic and drug delivery tool Statin PLGA nanoparticlesMI/hAdSCsIn vivo: male nude mice (BALB/c nu/nu)A small number of intravenously administered SimNP-loaded AdSCs improve cardiac function following MI, stimulating endogenous cardiac regeneration in the infarcted myocardium. [244]
Tracking of treatmentColloidal nanoparticles containing europium loaded on collagen matrixMI/Lewis rat BM-MSCsIn vivo: female Fischer ratCollagen matrix enhance transplanted MSC retention and reduce migration of the cells into remote organs as tracked by the radioactive NPs. [211]
Tracking and magnetic targeting of treatment Superparamagnetic iron microspheresMI/Rat CDCsIn vitro: rat CDCsIn vivo: female WKY rats In vitro: ↓caspase 3+, ↓TUNEL+.[212]
In vivo: enhanced cell engraftment, with attenuated left ventricular remodeling and increased ejection fraction. ↑GFP+, ↑Ki67+ CMs, and ↑GFP/c-KIT+ cells.
Imaging and therapeutic by magnetic targeting Ferumoxytol (FDA-approved SPIONs) nanoparticles linked by heparin sulfate and protamine sulfate MI/Human and ratCDCsIn vitro: hCDCs and rCDCsIn vitro: ↓TUNEL+, ↓ROS and ↑CCK-8, ↑Ki67. [213]
In vivo: augmentation of acute cell retention and attenuation of left ventricular remodeling, 3 wk after treatment by MRI, fluorescence imaging, qPCR.
In vivo: female WKY rats
Imaging and tracking for differentiation Potassium niobate harmonic nanoparticles stabilized by polyethylene glycol Non-diseased/ESC-derived CMsIn vitro: mouse ESC (CGR8 cell line)Monitoring at high acquisition speed the rhythmic contractions of ESC-derived CMs beating within 3D cluster.[245]
Therapeutic by magnetic guidance of NPsIron oxide nanoparticle-incorporated nanovesicles (exosome memetic nanovesicles); (IONP-NVs)MI/MSCsIn vitro: rat CM, rat CFs, macrophage, HUVECs.In vitro: under hypoxia IONP-MSCs exert[217]
Antiapoptotic effect on CMs: ↓caspase 3+, ↑Cx43, ↑PI3K.
Antifibrotic effect on CFs: ↑Cx43, ↓TGFβ1, ↓αActa2, ↓MMP2, ↓MMP9.
Anti-inflammatory effect on macrophage.
In vivo: Fischer 344 rats
Proangiogenic effect on HUVECs: ↑tube formation, ↑EC migration.
In vivo: magnetic guidance increases IONP-MSCs retention within the infarcted heart, with early shift from inflammatory stage to reparative stage.
Table 2 Completed clinical trials reporting on the use of cardiac derived stem cells in cardiovascular disorders
Study name, NCT Number
Start year
Study phase
Cardio-vascular disease
Patients number
Type of cardiac stem cells/origin
Route of delivery /count of cells
Timing of cell delivery
Follow up times
CADUCEUS, 0089336020091IHD17Autologous CDCs/endomyocardial biopsiesIC/12.5-25 × 1061.5-3 m post STEMI6 moMRISignificant reduction in infarct size [221]
Significant growth in viable mass global LVEF remains unchanged LVEF and volumes.
ALLSTAR, 014584052017I/IIIHD90Allogenic CDCs/endomyocardial biopsiesIC/25 × 106< 5 d post MI12 moMRINo effect on scar sizeAttenuation of post infarct cardiac remodeling[222]
Improvement in LV end diastolic volume
ALCADIA, 009810062010ICHFIHDVD6Autologous hCSCs/endomyocardial biopsies + bFGF on gelatin hydrogel sheetIM/0.5 × 106 /kg and 200 µg of bFGFAt CABG12 moNot mentionedDecreased scar size[229]
ESCORT, 0205790002013IIHD6ESCs-derived ISL1+ CSCsEpicardial patch 5-10 × 106 CSCs embedded in a fibrin patchAt CABG18 moCTSymptomatically improved patients with an increased systolic motion of the cell- treated segments.[223]
PET scan
The protocol generated a highly purified population of cardiovascular progenitors.
One patient died of heart failure after 22 mo
CAREMI, 02439398.2014I/IIAMI55Allogeneic hCSCs/right atrial appendageIC/35 × 106 cells5 to 7 d after successful reperfusion of AMI by PCI or 8 d from symptoms onset1 wk, 1, 2, 3, 4, 5, 6, 9 and 12 moMRIAllogeneic CSCs intracoronary infusion early after AMI is safe and anticipates reasonable efficacy outcomes[227]
CONSERT-HF, 02501811.2015IIHF125Autologous c-KIT+ CPCs + MSCs/right ventricular endocardial biopsy + Bone marrow aspirationTrans endocardial/150 × 106 MSCs and 5 × 106 CPCs14 wk after cell harvest6 and 12 moMRIIncreased LVEF [230]
Decrease in infarct size with LV end systolic volume reduction.
Strong safety profile
HOPE, 024859382015I\IICM secondary to DMD25Allogeneic CDCsIC/75 × 106Not specified12 moMRISignificant scar reduction improvement in inferior wall systolic thickening compared to the usual care group.[228]
CDCs are generally safe and well-tolerated
DYNAMIC, 022936032014IIdiopathic dilated CM42Allogeneic CDC/not specifiedIC/Stepwise dose escalationNot specified6, 12 moECGNot published_
Cardiac enzymes
TICAP, 012738572011IHLHS7Autologous CDCs/right atrial appendageIC/0.3 × 106 cells/kg1 m after cardiac surgery36 moEchoSafety of the procedure [233]
Increased right ventricle ejection fraction
Improved somatic growth
Reduced heart failure status
Perseus, 018297502013IIHLHS34Autologous CDCs/not specifiedIC/0.3 × 106 cells/kg4 to 9 wk after surgery3 and 12 mo follow-upEchoMRIQuestionnaireSignificant improve of ventricular function [231]
Improved somatic growth, and quality of life
Reduced heart failure status and cardiac fibrosis compared with baseline
Table 3 Ongoing and future expected clinical trials
Study name, NCT number
Year of study start
Study phase
Cardiovascular disease
Number of patients
Type of cardiac cells
Route of delivery
Regress-HFpEF, 029417052017IISymptomatic hypertensive heart disease induced HFpEF40Allogeneic CDCsIC
APOLLON trial, 027819222016IIIHLHS40Autologous CSCsIC
CHILD, 034068842019IHLHS32Autologous c-KIT+ cellsIM
ALPHA, 031452982017IPAH26Allogeneic CDCIV
TAC-HFT-II, 025032802025I/IIIHF0 enrollment until nowAutologous combination of MSCs and CSCsTrans endocardial Injection