Biologically active constituents of the secretome of human W8B2+ cardiac stem cells

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.

Human pluripotent stem cell-derived cardiomyocytes as a target platform for paracrine protection by cardiac mesenchymal stromal cells

“…1, 2, 3 and 4 5 . In addition, they resemble certain human cardiac mesenchymal cells reported previously 11 , albeit without need of histone deacetylase depletion, and correspond better, by this signature, to the cardiac-resident MSC 27 and closely related populations 6,13 . Samples from all five patients tested suppressed cell death induced by menadione in the two human cardiomyocyte lines (p < 0.0001; Fig.…”

“…Proposed approaches include diverse cell therapies aimed at the generation of new cardiac muscle, by grafting putative precursors such as bone marrow stem cells, heart-derived cardiac progenitor/stem cells, cardiac mesenchymal cells, cardiosphere-derived cells, and established cardiomyocytes made from pluripotent stem cells 2 , 3 . However, the persistence of grafted cells in recipient hearts is brief, at least in the pre-clinical setting where it can be tracked conclusively, leading to a persuasive two-fold paradigm shift 4 – 13 . First, therapeutic grafting to supply de novo contractile myocytes themselves is now understood to require alternatives beyond simplistic injections of naked cells, an aspect ripe for biomaterials and tissue engineering strategies 14 .…”

Secretome Analysis Performed During in vitro Cardiac Differentiation: Discovering the Cardiac Microenvironment

“…Then, the characterization of conditioned medium (CM) of mouse ESC at two time points of spontaneous cardiac differentiation identified approximately 150 proteins (Farina et al, 2011). Considering specifically the secretome of cardiac progenitors, either from mouse or human, various cytokines, growth factors, and other proteins were described in the CM and microvesicles of these cells Park et al, 2016;Nie et al, 2018;Samal et al, 2019). As an example, Sharma et al (2017) isolated human cardiac progenitor cells (CPCs) from newborns and adults and compared the composition and functionality of their respective CMs.…”

Rescue of degenerating neurons and cells by stem cell released molecules: using a physiological renormalization strategy

“…; Nie et al. ), and known to be contained in exosomes. Neurons are particular vulnerable to stress because they do not make their own HSPs (Oza et al.…”

“…Bone marrow stem cells are distinct from neural stem cells for example, and each cell type will release a pool of 100s of molecules that act collectively in a synergistic manner to promote homeostasis, such as proteostasis and cellulostasis (cell survival), for example (Nie et al. ).…”