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Pluripotent Stem Cell Derived Cardiac Cells for Myocardial Repair
Published on: February 3, 2017
Human pluripotent stem cell-derived cardiomyocytes as a target platform for paracrine protection by cardiac
Chrystalla Constantinou1, Antonio M A Miranda1,2, Patricia Chaves1,2
1National Heart and Lung Institute, Imperial College London, Du Cane Road, London, W12 0NN, UK.
Insights
Cardiac mesenchymal stromal cells (cMSCs) protect human heart cells from death via secreted factors. This suggests cMSC secretomes could be cell-free therapies for heart attack survivors, improving cardiac function.
Area of Science:
- Cardiovascular Biology
- Regenerative Medicine
- Cell Therapy
Background:
- Ischemic heart disease is a leading cause of death, with survivors facing heart failure risk.
- Cell therapies improve cardiac function post-injury, likely through paracrine signaling, though mechanisms in humans are unclear.
- Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) offer a model to study human cardiac cell responses.
Purpose of the Study:
- To investigate the cardioprotective effects of paracrine signals from cardiac mesenchymal stromal cells (cMSCs) on human cardiomyocytes (hPSC-CMs).
- To determine if cMSCs can prevent cardiomyocyte death and preserve cardiac function through secreted factors.
- To explore the potential of cMSC secretomes as cell-free therapeutic products for ischemic heart disease.
Main Methods:
- Co-culture and conditioned medium studies using hPSC-CMs treated with cMSC-derived factors.
- Comparison of cMSC protection with factors from fibroblasts (mouse tail tip and human skin).
- Transcriptomic profiling and functional analyses of apoptosis suppression and mitochondrial potential preservation.
- In vivo studies in mice involving injection of cMSC-conditioned media into the infarct border zone.
Main Results:
- cMSCs significantly inhibited human cardiomyocyte death, unlike fibroblasts.
- The cMSC secretome suppressed apoptosis and maintained mitochondrial transmembrane potential in hPSC-CMs.
- Protection was observed to be independent of exosomes under tested conditions.
- In vivo, cMSC-conditioned media reduced local apoptotic cardiomyocytes by over 70% in mouse infarct models.
Conclusions:
- hPSC-CMs serve as a valuable human model for studying extracellular signals involved in cardiac survival.
- Human cMSCs demonstrate significant cardioprotective capabilities through their secretome.
- The cMSC secretome or its components represent promising candidates for cell-free therapeutic strategies in treating cardiac injury.
Abstract:
Ischemic heart disease remains the foremost cause of death globally, with survivors at risk for subsequent heart failure. Paradoxically, cell therapies to offset cardiomyocyte loss after ischemic injury improve long-term cardiac function despite a lack of durable engraftment. An evolving consensus, inferred preponderantly from non-human models, is that transplanted cells benefit the heart via early paracrine signals. Here, we tested the impact of paracrine signals on human cardiomyocytes, using human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) as the target of mouse and human cardiac mesenchymal stromal cells (cMSC) with progenitor-like features. In co-culture and conditioned medium studies, cMSCs markedly inhibited human cardiomyocyte death. Little or no protection was conferred by mouse tail tip or human skin fibroblasts. Consistent with the results of transcriptomic profiling, functional analyses showed that the cMSC secretome suppressed apoptosis and preserved cardiac mitochondrial transmembrane potential. Protection was independent of exosomes under the conditions tested. In mice, injecting cMSC-conditioned media into the infarct border zone reduced apoptotic cardiomyocytes > 70% locally. Thus, hPSC-CMs provide an auspicious, relevant human platform to investigate extracellular signals for cardiac muscle survival, substantiating human cardioprotection by cMSCs, and suggesting the cMSC secretome or its components as potential cell-free therapeutic products.
