Cardiac stem cells: Current knowledge and future prospects

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	Outcomes	Ref.
Tissue engineering	Semi-crystalline PLLA nanostructured membranes among several PLGA membranes	Non-diseased/primary CMs	In vitro: electrospun matrices were used as scaffolds for generating cardiac tissue constructs	Nanostructured 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 engineering	ECM-mimicking nanofibrous PLLA scaffolds with porous structure (porous NF PLLA) of high interconnection for cardiac tissue formation	Non-diseased/mouse ESCs	In vitro: CPCs with porous NF PLLA	In 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.
		CPCs
Tissue engineering/therapeutic	Biodegradable ANF	MI/hiPSCs-CMs	In 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 ECM	Non diseased/Resident CSCs	In vitro: rat CMs from 2-d old neonatal rats	Combination 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/CPCs	In vitro: clonogenic CPCs	In 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 complex	MI/cSCA-1+ cardiac progenitors Other stem cells BM, SM, AMC	In vivo: Wild-type mice (C57Bl/6J); Adult GFP transgenic mice	cSCA-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 surface	MI/Human CSCs	In situ: characterization	In 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 nanoparticles	MI/hAdSCs	In 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 treatment	Colloidal nanoparticles containing europium loaded on collagen matrix	MI/Lewis rat BM-MSCs	In vivo: female Fischer rat	Collagen 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 microspheres	MI/Rat CDCs	In 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 ratCDCs	In vitro: hCDCs and rCDCs	In 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 CMs	In 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 NPs	Iron oxide nanoparticle-incorporated nanovesicles (exosome memetic nanovesicles); (IONP-NVs)	MI/MSCs	In 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.

AMC: Adipose tissue-derived mesenchymal cell; ANF: Aligned PLGA nanofibers; Au-Lap NP: Gold and laponite nanoparticle; BrdU: Bromodeoxyuridine cell proliferation assay; CCK-8: Cell counting kit-8; CF: Cardiac fibroblast; CM: Cardiomyocyte; CMMP: Cell-mimicking microparticle; CPC: Cardiac progenitor cell; CTLC: Cardiac tissue-like construct; cTnl: Cardiac troponin 1; FDA: Food and Drug Administration; ECM: Extracellular matrix; ESC: Embryonic stem cell; hAdSC: Human adipose-derived stem cell; HUVEC: Human umbilical cord vein endothelial cell; IONP: Iron oxide nanoparticle; MRI: Magnetic resonance imaging; NF: Nanofibrous; MI: Myocardial infarction; MMP: Matrix metalloproteinase; NRCM: Neonatal rat cardiomyocyte; PLGA: Poly D,L-lactic-co-glycolic acid; PLLA: Poly (L-lactic acid); PM: Puramatrix™; qPCR: Quantitative polymerase chain reaction; SM: Skeletal myoblast; SPION: Superparamagnetic iron oxide NP; TdT: Terminal deoxynucleotidyl transferase apoptotic assay; TUNEL: Terminal deoxynucleotidyl transferase dUTP nick end labeling apoptotic assay; vWF: von-Willebrand factor; WKY: Wistar-Kyoto; αSMA: Alpha smooth muscle actin; 3-D: Three-dimensional.