The Evolution of the Stem Cell Theory for Heart Failure

• Varied sources of therapeutic cells and low repair ability of the failing heart contribute to mixed results in clinical trials.
• Consensus is still lacking concerning the appropriate type of therapeutic stem cells.
• A clear understanding of cardiac development and adult cardiogenesis might increase the efficiency of regenerative therapies.
• Delivery of stem cell-derived paracrine factor alone to the damaged heart may be sufficient to activate repair mechanisms.

ABSTRACTVarious stem cell-based approaches for cardiac repair have achieved encouraging results in animal experiments, often leading to their rapid proceeding to clinical testing. However, freewheeling evolutionary developments of the stem cell theory might lead to dystopian scenarios where heterogeneous sources of therapeutic cells could promote mixed clinical outcomes in un-stratified patient populations. This review focuses on the lessons that should be learnt from the first generation of stem cell-based strategies and emphasizes the absolute requirement to better understand the basic mechanisms of stem cell biology and cardiogenesis. We will also discuss about the unexpected “big bang” in the stem cell theory, “blasting” the therapeutic cells to their unchallenged ability to release paracrine factors such as extracellular membrane vesicles. Paradoxically, the natural evolution of the stem cell theory for cardiac regeneration may end with the development of cell-free strategies with multiple cellular targets including cardiomyocytes but also other infiltrating or resident cardiac cells.