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Donor MSCs release apoptotic bodies to improve myocardial infarction via autophagy regulation in recipient cells.

ABSTRACT: Mesenchymal stem cell (MSC) transplantation has been widely applied as a potential therapeutic for multiple diseases. However, the underlying therapeutic mechanisms are not fully understood, especially the paradox between the low survival rate of transplanted cells and the beneficial therapeutic effects generated by these cells. Herein, in a myocardial infarction (MI) model, we found that transplanted MSCs released apoptotic bodies (ABs) to enhance angiogenesis and improve cardiac functional reclovery via regulating macroautophagy/autophagy in the recipient endothelial cells (ECs). Mechanistically, after local transplantation, MSCs underwent extensive apoptosis in the short term and released ABs, which were engulfed by the recipient ECs. Then, in the ECs, ABs activated lysosome functions and promoted the expression of TFEB (transcription factor EB), which is a master gene in lysosomal biogenesis and autophagy. Finally, the increase in TFEB enhanced autophagy-related gene expression in ECs and promoted angiogenesis and cardiac functional recovery after MI. Collectively, we found that apoptotic donor MSCs promote angiogenesis via regulating autophagy in the recipient ECs, unveiling the role of donor cell apoptosis in the therapeutic effects generated by cell transplantation. Abbreviations: 3-MA: 3-methyladenine; ABs: apoptotic bodies; BECN1: beclin 1; CASP3: caspase 3; CQ: chloroquine; ECs: endothelial cells; EVs: extracellular vesicles; LAMP1: lysosomal-associated membrane protein 1; LVEF: left ventricular ejection fraction; LVFS: left ventricular fractional shortening; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MI: myocardial infarction; MSC: mesenchymal stem cell; NO: nitric oxide; TFEB: transcription factor EB; TUNEL: TdT-mediated dUTP Nick-End Labeling.

SUBMITTER: Liu H

PROVIDER: S-EPMC7751634 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Aim:The acute phase of myocardial infarction (MI) is accompanied by edema contributing to tissue damage and disease outcome. Here, we aimed to identify the mechanism whereby vascular endothelial growth factor (VEGF)-A induces myocardial edema in the acute phase of MI to eventually promote development of therapeutics to specifically suppress VEGFA-regulated vascular permeability while preserving collateral vessel formation. Methods and Results:VEGFA regulates vascular permeability and edema by activation of VEGF receptor-2 (VEGFR2), leading to induction of several signaling pathways including the cytoplasmic tyrosine kinase c-Src. The activated c-Src in turn phosphorylates vascular endothelial (VE)-cadherin, leading to dissociation of endothelial adherens junctions. A particular tyrosine at position 949 in mouse VEGFR2 has been shown to be required for activation of c-Src. Wild-type mice and mice with phenylalanine replacing tyrosine (Y) 949 in VEGFR2 (Vegfr2 Y949F/Y949F ) were challenged with MI through permanent ligation of the left anterior descending coronary artery. The infarct size was similar in wild-type and mutant mice, but left ventricular wall edema and fibrinogen deposition, indicative of vascular leakage, were reduced in the Vegfr2 Y949F/Y949F strain. When challenged with large infarcts, the Vegfr2 Y949F/Y949F mice survived significantly better than the wild-type strain. Moreover, neutrophil infiltration and levels of myeloperoxidase were low in the infarcted Vegfr2 Y949F/Y949F hearts, correlating with improved survival. In vivo tyrosine phosphorylation of VE-cadherin at Y685, implicated in regulation of vascular permeability, was induced by circulating VEGFA in the wild-type but remained at baseline levels in the Vegfr2 Y949F/Y949F hearts. Conclusion:Suppression of VEGFA/VEGFR2-regulated vascular permeability leads to diminished edema without affecting vascular density correlating with improved myocardial parameters and survival after MI.

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Donor MSCs release apoptotic bodies to improve myocardial infarction via autophagy regulation in recipient cells.

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