Extracellular Vesicles From Notch Activated Cardiac Mesenchymal Stem Cells Promote Myocyte Proliferation and Neovasculogenesis

Abstract

Cardiac mesenchymal stem cells (C-MSCs) are a novel mesenchymal stem cell (MSC) subpopulation derived from cardiac tissue, which are reported to be responsible for cardiac regeneration. Notch signaling is believed to aid in cardiac repair following myocardial injury. In this study, we have investigated the role of extracellular vesicles (EVs) from Notch1 engineered C-MSCs on angiogenesis and cardiomyocyte (CM) proliferation in ischemic myocardium. C-MSCs were isolated from Notch1 flox mice (C-MSC Notch1FF). Notch1 gene deletion was accomplished by adenoviral vectormediated Cre recombination, and Notch1 overexpression was achieved by overexpression of Notch1 intracellular domain (N1ICD). EVs were isolated by using the size exclusion column method. Proteomic composition of EV was carried out by mass spectrometry. A mouse myocardial infarction (MI) model was generated by permanent left anterior descending (LAD) coronary artery ligation. Intramyocardial transplantation of Notch1 knockout C-MSCs (C-MSCs Notch1KO) did not have any effect on cardiac function and scar size. On the other hand, transplantation of N1ICD-overexpressing C-MSCs (C-MSCs N1ICD) showed significant improvement in cardiac function and attenuation of fibrosis as compared to the control (PBS) group and non-modified C-MSC groups. C-MSCs N1ICD differentiated into smooth muscle cells and formed new vessels. Proteomics profiling identified several proteins, such as lysyl oxidase homolog-2 and biglycan, as highly enriched proteins in EV-C-MSCs N1ICD. Go term analysis indicated that EV-C-MSCs N1ICD were enriched with bioactive factors, potent prorepair proteins responsible for cell migration and proliferation. EV-C-MSCs Notch1FF and EV-C-MSCs N1ICD were strongly proangiogenic under both in vitro and in vivo conditions. EV-C-MSCs N1ICD caused dense tube formation in vitro and increased neovasculogenesis in the peri-infarct area in vivo. Furthermore, EV-C-MSCs N1ICD attenuated endothelial cell (EC) and CM apoptosis under oxidative stress and ischemic injury. Similarly, EV-C-MSC Notch1FF and EV-C-MSC N1ICD treatment improved cardiac

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“…6e, f). EVs are small, membrane-bound vesicles released from cells that can transport cargo including DNA, mRNAs, microRNAs (miRNAs), and proteins [16,18]. The secreted EVs carrying specific miRNA from Givi-MPC likely facilitated angiogenesis [16].…”

Could Mesenchymal Stem Cell-Derived Exosomes Be a Therapeutic Option for Critically Ill COVID-19 Patients?

“…The authors suggested that platelet-derived growth factor D (PDGF-D), which was enriched in MSC-derived vesicles, was mainly responsible for the Akt exosome-mediated improvement of myocardial repair. A more recent study by Xuan and colleagues identified Notch1 as a potent modulator of angiogenesis and cardiomyocyte proliferation into ischemic mice hearts following coronary heart ligation [ 142 ]. The role of Notch1 signaling in inducing cardiac angiogenesis during ischemia and enhancing survival of cardiac cells is well established [ 143 ].…”

“…The role of Notch1 signaling in inducing cardiac angiogenesis during ischemia and enhancing survival of cardiac cells is well established [ 143 ]. The injection of MSC-derived EVs over-expressing Notch1 intracellular domain (NICD) in ischemic myocardium led to decreased infarct size, improved cardiac function, and increased arteriole density in the peri-infarct area, 1 month after AMI [ 142 ]. Moreover, Teng and coworkers indicated that the beneficial effect of MSC-derived exosomes on infarcted rat hearts is mainly dependent on their angiogenesis-promoting activity [ 144 ].…”

“… Schematic diagram showing the beneficial therapeutic effects of MSC-derived EVs (MVs or exosomes) in heart affected by acute myocardial infarction (AMI). These are reduction of the inflammatory response [ 139 , 144 , 148 ], reduction of cardiac fibrosis, reduction of cardiomyocyte apoptosis [ 145 , 146 , 148 , 149 , 151 ], promotion of angiogenesis [ 140 , 141 , 142 , 144 ], and induction of cardiomyocytes autophagy [ 151 ]. …”

Tumor Microenvironment Uses a Reversible Reprogramming of Mesenchymal Stromal Cells to Mediate Pro-tumorigenic Effects

“…Mesenchymal stromal cells (MSCs) are multipotent stem cells capable of differentiating into various cell types of the mesodermal lineage, including adipocytes, endothelial cells, fibroblasts, chondrocytes, osteoblasts, and myocytes ( Dominici et al, 2006 ), and possibly into non-mesodermal cell types, such as neural, pancreatic, hepatic, and gastric cells ( Oswald et al, 2004 ; Cislo-Pakuluk and Marycz, 2017 ; Luo et al, 2020 ; Xuan et al, 2020 ). They are a heterogeneous mesenchymal cell population, which resides in the stroma of various tissues and organs and expressing the membrane markers CD105, CD73, and CD90, but not HLA-DR, CD14, CD19, CD31, CD34, and CD45 ( Dominici et al, 2006 ; Nwabo Kamdje et al, 2011 ).…”