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Pluripotent Stem Cell Derived Cardiac Cells for Myocardial Repair
Published on: February 3, 2017
Evaluating the Reparative Potential of Secretome from Patient-Derived Induced Pluripotent Stem Cells during
Elise Rody1, Jeremy Zwaig2, Ida Derish2,3
1Department of Surgery, Division of Cardiac Surgery, McGill University Health Center, Montreal, QC H4A 3J1, Canada.
Insights
Induced pluripotent stem cell secretomes protect heart cells from injury. However, secretomes from healthy donors are more effective than those from dilated cardiomyopathy donors for improving cardiovascular outcomes.
Area of Science:
- Cardiovascular Research
- Stem Cell Biology
- Regenerative Medicine
Background:
- Cardiomyocytes (CMs) have limited regenerative capacity, making heart attack recovery challenging.
- Stem cell therapies show promise for cardiac repair, but cell engraftment is minimal, leading to interest in cell-free approaches.
- Induced pluripotent stem cells (iPSCs) offer a viable source for cell-free therapies due to their regenerative potential and accessibility.
Purpose of the Study:
- To investigate the therapeutic potential of iPSC secretomes in treating ischemia-reperfusion (IR) injury in CMs.
- To determine if donor health status (healthy vs. dilated cardiomyopathy) influences the efficacy of iPSC secretome therapy.
- To elucidate the protein content and functional impact of iPSC secretomes on injured CMs.
Main Methods:
- iPSCs from healthy and DCM donors were cultured, and their secretomes collected.
- Secretome protein content was analyzed using mass spectrometry.
- AC16 immortalized CMs were subjected to hypoxia/reperfusion (IR) injury and treated with iPSC secretomes.
Main Results:
- iPSC secretomes, irrespective of donor health, upregulated cell survival pathways and improved CM survival under IR conditions.
- Healthy donor-derived secretomes showed higher expression of calcium contractility-related proteins compared to DCM donor secretomes.
- Only healthy donor secretomes significantly improved intracellular calcium concentrations in injured CMs.
Conclusions:
- iPSC secretome therapy demonstrates potential for protecting CMs against IR injury.
- Donor health status is a critical factor, with healthy donor secretomes exhibiting superior efficacy.
- These findings highlight donor-specific variations in iPSC secretome regenerative potential for cardiovascular applications.
Abstract:
During a heart attack, ischemia causes losses of billions of cells; this is especially concerning given the minimal regenerative capability of cardiomyocytes (CMs). Heart remuscularization utilizing stem cells has improved cardiac outcomes despite little cell engraftment, thereby shifting focus to cell-free therapies. Consequently, we chose induced pluripotent stem cells (iPSCs) given their pluripotent nature, efficacy in previous studies, and easy obtainability from minimally invasive techniques. Nonetheless, using iPSC secretome-based therapies for treating injured CMs in a clinical setting is ill-understood. We hypothesized that the iPSC secretome, regardless of donor health, would improve cardiovascular outcomes in the CM model of ischemia-reperfusion (IR) injury. Episomal-generated iPSCs from healthy and dilated cardiomyopathy (DCM) donors, passaged 6-10 times, underwent 24 h incubation in serum-free media. Protein content of the secretome was analyzed by mass spectroscopy and used to treat AC16 immortalized CMs during 5 h reperfusion following 24 h of hypoxia. IPSC-derived secretome content, independent of donor health status, had elevated expression of proteins involved in cell survival pathways. In IR conditions, iPSC-derived secretome increased cell survival as measured by metabolic activity (p < 0.05), cell viability (p < 0.001), and maladaptive cellular remodelling (p = 0.052). Healthy donor-derived secretome contained increased expression of proteins related to calcium contractility compared to DCM donors. Congruently, only healthy donor-derived secretomes improved CM intracellular calcium concentrations (p < 0.01). Heretofore, secretome studies mainly investigated differences relating to cell type rather than donor health. Our work suggests that healthy donors provide more efficacious iPSC-derived secretome compared to DCM donors in the context of IR injury in human CMs. These findings illustrate that the regenerative potential of the iPSC secretome varies due to donor-specific differences.
