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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 Notch1flox mice (C-MSCNotch1 FF). Notch1 gene deletion was accomplished by adenoviral vector-mediated 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-MSCsNotch1 KO) did not have any effect on cardiac function and scar size. On the other hand, transplantation of N1ICD-overexpressing C-MSCs (C-MSCsN1ICD) showed significant improvement in cardiac function and attenuation of fibrosis as compared to the control (PBS) group and non-modified C-MSC groups. C-MSCsN1ICD 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-MSCsN1ICD. Go term analysis indicated that EV-C-MSCsN1ICD were enriched with bioactive factors, potent pro-repair proteins responsible for cell migration and proliferation. EV-C-MSCs Notch1FF and EV-C-MSCsN1ICD were strongly proangiogenic under both in vitro and in vivo conditions. EV-C-MSCsN1ICD caused dense tube formation in vitro and increased neovasculogenesis in the peri-infarct area in vivo. Furthermore, EV-C-MSCsN1ICD attenuated endothelial cell (EC) and CM apoptosis under oxidative stress and ischemic injury. Similarly, EV-C-MSCNotch1 FF and EV-C-MSCN1ICD treatment improved cardiac function and decreased fibrosis in mice post-MI. EV-C-MSCsN1ICD were very effective in improving cardiac function and decreasing fibrosis. Notch1 signaling is a strong stimulus for cardiac regeneration by C-MSCs. EVs secreted by Notch1-overexpressing C-MSCs were highly effective in preventing cell death, promoting angiogenesis and CM proliferation, and restoring cardiac function post-MI. Overall, these results suggest that Notch1 overexpression may further enhance the effectiveness of EVs secreted by C-MSCs in cell-free therapy.

SUBMITTER: Xuan W

PROVIDER: S-EPMC7047205 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Xuan Wanling W Khan Mahmood M Ashraf Muhammad M

Frontiers in cell and developmental biology 20200221

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<sup>flox</sup> ...[more]

PMID: 32154243

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Project description:Background: Neonatal encephalopathy caused by hypoxia-ischemia (HI) is a major cause of childhood mortality and disability. Stem cell-based regenerative therapies seem promising to prevent long-term neurological deficits. Our previous work in neonatal HI revealed an unexpected interaction between mesenchymal stem/stromal cells (MSCs) and the brains' microenvironment leading to an altered therapeutic efficiency. MSCs are supposed to mediate most of their therapeutic effects in a paracrine mode via extracellular vesicles (EVs), which might be an alternative to cell therapy. In the present study, we investigated the impact of MSC-EVs on neonatal HI-induced brain injury. Methods: Nine-day-old C57BL/6 mice were exposed to HI through ligation of the right common carotid artery followed by 1 h hypoxia (10% oxygen). MSC-EVs were injected intraperitoneally 1, 3, and 5 days after HI. One week after HI, brain injury was evaluated by regional neuropathological scoring, atrophy measurements and immunohistochemistry to assess effects on neuronal, oligodendrocyte and vessel densities, proliferation, oligodendrocyte maturation, myelination, astro-, and microglia activation. Immunohistochemistry analyses were complemented by mRNA expression analyses for a broad set of M1/M2- and A1/A2-associated molecules and neural growth factors. Results: While total neuropathological scores and tissue atrophy were not changed, MSC-EVs significantly protected from HI-induced striatal tissue loss and decreased micro- and astroglia activation. MSC-EVs lead to a significant downregulation of the pro-inflammatory cytokine TNFa, accompanied by a significant upregulation of the M2 marker YM-1 and the anti-inflammatory cytokine TGFb. MSC-EVs significantly decreased astrocytic expression of the A1 marker C3, concomitant with an increased expression of neural growth factors (i.e., BDNF, VEGF, and EGF). These alterations were associated with an increased neuronal and vessel density, coinciding with a significant increase of proliferating cells in the neurogenic sub-ventricular zone juxtaposed to the striatum. MSC-EV-mediated neuroprotection went along with a significant improvement of oligodendrocyte maturation and myelination. Conclusion: The present study demonstrates that MSC-EVs mediate anti-inflammatory effects, promote regenerative responses and improve key developmental processes in the injured neonatal brain. The present results suggest different cellular target mechanisms of MSC-EVs, preventing secondary HI-induced brain injury. MSC-EV treatment may be a promising alternative to risk-associated cell therapies in neonatal brain injury.

Dataset Information

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

Publications

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

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