A New Paradigm in Cardiac Regeneration: The Mesenchymal Stem Cell Secretome

Table 1

Summary of molecules released by MSCs, via either direct secretion or exosomes and microvesicles, and their diverse beneficial effects in cardiovascular repair. The table includes relevant studies demonstrating specific molecule expression/secretion by MSCs and their respective effects.

Way of secretion	Molecule	Functional role in cardiovascular repair	References
Direct secretion	Adrenomedullin	Angiogenic and cardioprotective factor	[13]
	Angiogenin	LV remodeling attenuation through vasculogenesis	[31]
	Basic fibroblast growth factor (bFGF, FGF-2)	Vascular regeneration and attenuation of apoptotic pathways, leading to reduced remodeling	[32]
	CXCL12	Endothelial tube formation	[33]
	Cystatin C	Fibroblast chemoattraction	[34]
	Cysteine-rich angiogenic inducer (Cyr61)	Angiogenesis promotion	[35]
	Dickkopf-related proteins (Dkk)	JNK signaling activation, eventually resulting in cardiomyogenesis	[36]
	ECM structural proteins	Fibroblast chemoattraction	[34]
	Hepatocyte growth factor (HGF)	Mobilization of cardiac progenitor cells	[13]
	Hypoxic induced Akt regulated stem cell factor (HASF)	Cardiomyocytes survival improvement	[37]
	Insulin-like growth factor (IGF)	Antiapoptotic effect, angiogenesis promotion, and activation of resident CSCs	[38]
	Interleukin-1 (IL-1)	Angiogenesis promotion	[39]
	Interleukin-6 (IL-6)	VEGF induction	[13, 39]
	Leukemia inhibitory factor (LIF)	Mobilization of BM-progenitor cells and cardioprotection promotion	[40]
	Pigment epithelium-derived factor (PEDF)	Fibroblast chemoattraction	[34]
	Placental growth factor (PLGF)	Prevention of cell death of cardiomyocytes and endothelial cells	[13]
	Secreted Frizzled Related Protein (SFRP 2)	Fibrosis and apoptosis reduction, promotion of MSC self-renewal and engraftment	[41, 42]
	Soluble TNFR1 (sTNFR1)	Inflammatory response attenuation	[43]
	Stem cell-derived factor (SDF-1)	Stem cell recruitment and cardiomyocyte and MSC survival	[32, 44]
	TNF-α stimulated gene-6 (TSG-6)	Anti-inflammation action	[17]
	Vascular endothelial growth factor (VEGF)	Prevention of cell death of cardiomyocytes and endothelial cells	[13]
Exosomes	miR-19a	Akt/ERK signaling activation, through PTEN targeting	[45]
	miR22	Apoptosis reduction and ischemic CMCs injury improvement, through Mecp2 targeting	[46]
	20S proteasome subunits (PMSA 1-7)	Cardioprotection through proteolytic degradation of misfolded proteins	[47]
	Unknown	PMEC migration and vascularization improvement	[48]
	Unknown	Angiogenesis promotion	[49]
	Unknown	VEGF level incensement and angiogenesis promotion	[50]
	Unknown	Oxidative stress inhibition, PI3K/Akt pathway activation and inflammatory activity reduction	[51]
	Unknown	Hypoxic signal pathway inhibition	[52]
Microvesicles	miR221	CMCs apoptosis reduction and CMCs survival improvement	[53]
	Unknown	Endothelial cell proliferation and blood flow recovery	[54]