Abstract
The benefits of adult stem cells for repair of the heart have been attributed to the repertoire of salutary paracrine activities they appear to exert. We previously isolated human W8B2+ cardiac stem cells (CSCs) and found they powerfully influence cardiomyocytes and endothelial cells to collectively promote cardiac repair and regeneration. Here, the complexity of the W8B2+ CSC secretomes was characterised and examined in more detail. Using ion exchange chromatography to separate soluble proteins based on their net surface charge, the secreted factors responsible for the pro-survival activity of W8B2+ CSCs were found within the low and medium cation fractions. In addition to the soluble proteins, extracellular vesicles generated from W8B2+ CSCs not only exhibited pro-survival and pro-angiogenic activities, but also promoted proliferation of neonatal cardiomyocytes. These extracellular vesicles contain a cargo of proteins, mRNA and primary microRNA precursors that are enriched in exosomes and are capable of modulating collectively many of the cellular pathways involved in protein metabolism, cell growth, as well as cellular responses to stress and organisation of the extracellular matrix. Thus the W8B2+ CSC secretome contains a multitude of bioactive paracrine factors we have now characterised, that might well be harnessed for therapeutic application for cardiac repair and regeneration.
Highlights
The increasing prevalence and high mortality of heart disease demands a continued search for innovative approaches to management that might restore cardiac function
To determine whether the soluble proteins secreted by W8B2+ cardiac stem cells (CSCs) promote survival of the main cell types in the heart, cardiomyocytes and endothelial cells were subjected to hypoxia and serum deprivation, which simulates the in vivo ischaemic condition
This study clearly shows that the secretome of human W8B2+ CSC contains biological factors that are capable of promoting cell survival, angiogenesis and proliferation of cardiomyocytes
Summary
The increasing prevalence and high mortality of heart disease demands a continued search for innovative approaches to management that might restore cardiac function. The secretomes of stem cells have been shown to enrich the microenvironment of infarcted myocardium – these acting by various mechanisms including improving cell survival, enhancing angiogenesis, regulating inflammation, reducing adverse remodelling, and recruiting and activating endogenous resident stem cells for cardiac repair[8,9]. Intramyocardial transplantation of human W8B2+ CSCs into immunocompromised rats one week post myocardial infarction improved cardiac function and reduced maladaptive remodelling of the left ventricle for at least 3 weeks post-treatment[4] These beneficial effects can likely be attributed to the paracrine action of W8B2+ CSCs for there is no evidence that the transplanted cells engraft successfully nor differentiate into cardiovascular cell types in this setting[4]. We used proteomic and transcriptomic approaches to characterise and profile the secretome constituents of these unique W8B2+ CSCs
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