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Cardiopoietic stem cell therapy restores infarction-altered cardiac proteome

ABSTRACT: Cardiopoietic stem cells are in advanced clinical testing for ischemic heart failure. To profile their uncharted molecular influence on recipient hearts, systems proteomics was applied in a chronic murine model of infarction randomized with and without human cardiopoietic stem cell treatment. Four biological replicates are included from each of three separate groups, Control (Ctrl, n=4), myocardial infarction without treatment (MI, n=4), and MI with cardiopoietic stem cell treatment (CP, n=4). Athymic nude male mice (2-3 months of age) underwent left anterior descending coronary artery ligation (70-min occlusion followed by reperfusion). ST elevation on the electrocardiogram confirmed MI. Four weeks post-MI, animals were randomized into cohorts without (MI, n=4) or with (CP, n=4) cell therapy. Human CP cells were generated from bone marrow derived mesenchymal stem cells using an established cardiopoiesis protocol. Media (15 µL), with or without CP cells (600,000 cells/heart), were epicardially delivered in infarcted left ventricles.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

DISEASE(S): Cardiovascular System Disease

SUBMITTER: D Kent Arrell

LAB HEAD: Andre Terzic, MD, PhD

PROVIDER: PXD017381 | Pride | 2020-03-23

REPOSITORIES: Pride

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Cardiopoietic stem cell therapy restores infarction-altered cardiac proteome.

Arrell D Kent DK Rosenow Christian S CS Yamada Satsuki S Behfar Atta A Terzic Andre A

NPJ Regenerative medicine 20200312

Cardiopoietic stem cells have reached advanced clinical testing for ischemic heart failure. To profile their molecular influence on recipient hearts, systems proteomics was here applied in a chronic model of infarction randomized with and without human cardiopoietic stem cell treatment. Multidimensional label-free tandem mass spectrometry resolved and quantified 3987 proteins constituting the cardiac proteome. Infarction altered 450 proteins, reduced to 283 by stem cell treatment. Notably, cell ...[more]

PMID: 32194990

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Project description:OBJECTIVE: To understand the molecular pathways underlying the cardiac preconditioning effect of short-term caloric restriction (CR). BACKGROUND: Lifelong CR has been suggested to reduce the incidence of cardiovascular disease through a variety of mechanisms. However, prolonged adherence to a CR life-style is difficult. Here we show how short-term CR protects the mouse heart from ischemia. METHODS: Male 10-12 wk old C57bl/6 mice were randomly assigned to an ad libitum (AL) diet with free access to regular chow, or CR, receiving 30% less food over a period of 7 days (d), prior to myocardial infarction (MI) via permanent coronary ligation. Prior to MI (d8), the left ventricles (LV) of AL and CR mice were collected for Western blot, DNA and microRNA (miR) analyses. In separate groups, infarct size, cardiac hemodynamics and protein abundance of caspase 3 was measured at d2 post-MI. RESULTS: This short-term model of CR was associated with cardio-protection, as evidenced by decreased infarct size (18.5±2.4% vs. 26.6±1.7%, N=10/group; P=0.01). cDNA and miR profiles pre-MI (N=5/group) identified genes modulated by short-term CR to be associated with circadian clock, oxidative stress, immune function, apoptosis, metabolism, angiogenesis, cytoskeleton and extracellular matrix (ECM). Western blots pre-MI revealed CR-associated increases in phosphorylated Akt and GSK3ß, reduced levels of phosphorylated AMPK and mitochondrial related proteins PGC-1?, cytochrome C and cyclooxygenase (COX) IV, with no differences in the levels of phosphorylated eNOS or MAPK (ERK1/2; p38). CONCLUSIONS: Short-term CR for only 7d represents a preconditioning strategy that limits infarct size. It is associated with a unique gene and miR signature, including the activation of specific pro-survival kinases. These findings may have implications for therapeutic use of short-term CR. . Male 12 wk-old C57Bl/6 mice were obtained from Charles River (Montreal, PQ, Canada) and maintained for at least 2 weeks before experimentation. Animals were randomly assigned to AL, CR and Lira groups with no initial differences in body weights. AL group mice were allowed ad libitum diet. Lira group mice were injected with Liraglutide (Glucagon-like peptide-1 agonist) at a dose of 200 µg/Kg i.p., twice daily for 7 days which is a mild weight-loss inducing dose and had access to ad libitum food and water. CR group mice were put on a Caloric restriction diet (30% less than normal ad libitum caloric intake) for 7 days to induce weight loss comparable to Lira group mice. Mice for CR and AL were individually caged and their food intake was measured everyday between 10-11 am for 1 week to calculate the average daily food intake. CR mice were fed 30% less than the calculated mean daily AL food consumption. CR cages were inspected daily for any remaining food, and transferred to a new cage every day. For CR group, pre-weighed mouse chow pellets were placed in cages between 10-11 am every day. Body weights were recorded between 10-11 am before and after the 7 day study period. For pre-ischemic assessments, animals (n=5/group/assessment) were sacrificed on day-8 (pre-MI), hearts were immediately extracted, washed in sterile phosphate-buffered saline (PBS), with LV free walls dissected, snap frozen in liquid nitrogen and stored at -80o C.

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	ArrelletalCytoZipfolder.7z	Other
	ArrelletalMMOZipfolder.7z	Other
	Cyto_andromeda.7z	Other
	Cyto_txt.7z	Other
	MMO_andromeda.7z	Other