Browsing by Author "Benedict, Cindy"

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Open Access
Diabetes impairs cardioprotective function of endothelial progenitor cell-derived extracellular vesicles via H3K9Ac inhibition
(Theranostics, 2022) Huang, Grace; Cheng, Zhongjian; Hildebrand, Alycia; Wang, Chunlin; Cimini, Maria; Roy, Rakija; Lucchese, Anna Maria; Benedict, Cindy; Mallaredy, Vandana; Magadum, Ajit; Joladarashi, Darukeshwara; Thej, Charan; Gonzalez, Carolina; Trungcao, May; Garikipati, Venkata Naga Srikanth; Elrod, John W; Koch, Walter J; Kishore, Raj
Open Access
Interleukin-10 Deficiency Alters Endothelial Progenitor Cell–Derived Exosome Reparative Effect on Myocardial Repair via Integrin-Linked Kinase Enrichment
(Circulation Research, 2020-01-31) Yue, Yujia; Wang, Chunlin; Benedict, Cindy; Huang, Grace; Truongcao, May; Roy, Rajika; Cimini, Maria; Garikipati, Venkata Naga Srikanth; Cheng, Zhongjian; Koch, Walter J; Kishore, Raj
Rationale: Systemic inflammation compromises the reparative properties of endothelial progenitor cell (EPC) and their exosomes on myocardial repair, although the underlying mechanism of loss of function of exosomes from inflamed EPCs is still obscure. Objective: To determine the mechanisms of IL-10 (interleukin-10) deficient-EPC–derived exosome dysfunction in myocardial repair and to investigate if modification of specific exosome cargo can rescue reparative activity. Methods and Results: Using IL-10 knockout mice mimicking systemic inflammation condition, we compared therapeutic effect and protein cargo of exosomes isolated from wild-type EPC and IL-10 knockout EPC. In a mouse model of myocardial infarction (MI), wild-type EPC-derived exosome treatment significantly improved left ventricle cardiac function, inhibited cell apoptosis, reduced MI scar size, and promoted post-MI neovascularization, whereas IL-10 knockout EPC-derived exosome treatment showed diminished and opposite effects. Mass spectrometry analysis revealed wild-type EPC-derived exosome and IL-10 knockout EPC-derived exosome contain different protein expression pattern. Among differentially expressed proteins, ILK (integrin-linked kinase) was highly enriched in both IL-10 knockout EPC-derived exosome as well as TNFα (tumor necrosis factor-α)-treated mouse cardiac endothelial cell–derived exosomes (TNFα inflamed mouse cardiac endothelial cell–derived exosome). ILK-enriched exosomes activated NF-κB (nuclear factor κB) pathway and NF-κB–dependent gene transcription in recipient endothelial cells and this effect was partly attenuated through ILK knockdown in exosomes. Intriguingly, ILK knockdown in IL-10 knockout EPC-derived exosome significantly rescued their reparative dysfunction in myocardial repair, improved left ventricle cardiac function, reduced MI scar size, and enhanced post-MI neovascularization in MI mouse model. Conclusions: IL-10 deficiency/inflammation alters EPC-derived exosome function, content and therapeutic effect on myocardial repair by upregulating ILK enrichment in exosomes, and ILK-mediated activation of NF-κB pathway in recipient cells, whereas ILK knockdown in exosomes attenuates NF-κB activation and reduces inflammatory response. Our study provides new understanding of how inflammation may alter stem cell-exosome–mediated cardiac repair and identifies ILK as a target kinase for improving progenitor cell exosome-based cardiac therapies.
Open Access
Podoplanin neutralization improves cardiac remodeling and function after acute myocardial infarction.
(JCI insight, 2019-07) Cimini, Maria; Garikipati, Venkata Naga Srikanth; de Lucia, Claudio; Cheng, Zhongjian; Wang, Chunlin; Truongcao, May M; Lucchese, Anna Maria; Roy, Rajika; Benedict, Cindy; Goukassian, David A; Koch, Walter J; Kishore, Raj
Podoplanin, a small mucine-type transmembrane glycoprotein, has been recently shown to be expressed by lymphangiogenic, fibrogenic and mesenchymal progenitor cells in the acutely and chronically infarcted myocardium. Podoplanin binds to CLEC-2, a C-type lectin-like receptor 2 highly expressed by CD11bhigh cells following inflammatory stimuli. Why podoplanin expression appears only after organ injury is currently unknown. Here, we characterize the role of podoplanin in different stages of myocardial repair after infarction and propose a podoplanin-mediated mechanism in the resolution of post-MI inflammatory response and cardiac repair. Neutralization of podoplanin led to significant improvements in the left ventricular functions and scar composition in animals treated with podoplanin neutralizing antibody. The inhibition of the interaction between podoplanin and CLEC-2 expressing immune cells in the heart enhances the cardiac performance, regeneration and angiogenesis post MI. Our data indicates that modulating the interaction between podoplanin positive cells with the immune cells after myocardial infarction positively affects immune cell recruitment and may represent a novel therapeutic target to augment post-MI cardiac repair, regeneration and function.