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Human myocardial ischemia/reperfusion injury model to study cardiac stem cells activation and regeneration mechanisms

ABSTRACT: The importance of regenerative potential of cardiac stem/progenitor cells (CSCs) after acute myocardial infarction (AMI) has been emphasized in the last decade. Several studies have demonstrated that this cell population has a relevant role in myocardial repair, supported by the establishment of a paracrine cross-talk between CSCs and the injured tissue. However, the majority of current in vitro strategies to study these cells fails to include important modulators of CSC activity, such as the paracrine effect of cardiomyocytes (CMs) and the physicochemical changes occurring in tissue during Ischemia/Reperfusion (I/R) injury. In this work, we established the first human in vitro heterotypic model of myocardial I/R injury with human CSCs (hCSCs) and human induced pluripotent cell-derived cardiomyocytes (hiPSC-CMs) using transwell inserts. hCSCs response to I/R was characterized using advanced whole proteomic mass spectrometry-based tools that allowed us to propose new pathways in hCSCs regenerative process, including: cell cycle regulation inhibition, proliferation through EGF signaling, gluthathione-mediated reactive oxygen species detoxification, and signaling through several paracrine growth factors. The model established in this work contributes with new insights regarding hCSC biology in response to AMI and provides an important tool to study and modulate molecular mechanisms involved in the regenerative potential of CSCs.

INSTRUMENT(S): TripleTOF 6600

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Heart, Stem Cell, Cell Culture

SUBMITTER: Maria Sebastião

LAB HEAD: Paula Marques Alves

PROVIDER: PXD008156 | Pride | 2019-02-18

REPOSITORIES: Pride

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Human cardiac progenitor cell activation and regeneration mechanisms: exploring a novel myocardial ischemia/reperfusion in vitro model.

Sebastião Maria J MJ Serra Margarida M Pereira Rute R Palacios Itziar I Gomes-Alves Patrícia P Alves Paula M PM

Stem cell research & therapy 20190307 1

<h4>Background</h4>Numerous studies from different labs around the world report human cardiac progenitor cells (hCPCs) as having a role in myocardial repair upon ischemia/reperfusion (I/R) injury, mainly through auto/paracrine signaling. Even though these cell populations are already being investigated in cell transplantation-based clinical trials, the mechanisms underlying their response are still poorly understood.<h4>Methods</h4>To further investigate hCPC regenerative process, we established ...[more]

PMID: 30845956

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Project description:Whole-genome gene expression analysis has been successfully utilized to diagnose, prognosticate, and identify potential therapeutic targets for cardiovascular disease. However, the utility of this approach to identify outcome-related genes and dysregulated pathways following first-time myocardial infarction (AMI) remains unknown and may offer a novel strategy to detect affected expressome networks that predict long-term outcome. Whole-genome microarray and targeted cytokine expression profiling on blood samples from normal cardiac function controls and first-time AMI patients within 48-hours post-MI revealed expected differential gene expression profiles enriched for inflammation and immune-response pathways in AMI patients. To determine molecular signatures at the time of AMI that could prognosticate long-term outcomes, transcriptional profiles from sub-groups of AMI patients with (n=5) or without (n=22) any recurrent events over an 18-month follow-up were compared. This analysis identified 559 differentially expressed genes. Bioinformatic analysis of this differential gene set for associated pathways revealed 1) increasing disease severity in AMI patients is associated with a decreased expression of the developmental epithelial-to-mesenchymal transition, and 2) modulation of cholesterol transport genes that include ABCA1, CETP, APOA1, and LDLR is associated with clinical outcome. In conclusion, differentially regulated genes and modulated pathways were identified that predicted recurrent cardiovascular outcomes in first-time AMI patients. This cell-based approach for risk stratification in AMI warrants a larger study to determine the role of metabolic remodeling and regenerative processes required for optimal outcomes. A validated transcriptome assay could represent a novel, non-invasive platform to anticipate modifiable pathways and therapeutic targets to optimize long-term outcome for AMI patients. The overall experimental design includes blood samples from 21 control and 31 myocardial infaction patient groups. Among the 31patients, 5 patients have recurrent events. Microarray were peformed on the blood samples and comparisons of control vs patient and patients with recurrent events vs patients without recurrent events were performed to identify differential genes related to disease or patients groups with recurrent events for the following bioinformatic analysis.

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