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Recent interest in mechanisms of stem cell–mediated repair in the heart have spawned the paracrine hypothesis, which posits that stem cells release beneficial substances that improve regeneration and function of the injured and diseased myocardium. In support of this hypothesis are studies showing that stem cells release small membranous vesicles called exosomes that deliver beneficial cargo to other cells in the heart. However, in addition to exosomes, which are released by the unconventional secretory pathway, are many other potentially beneficial factors released by the unconventional and the conventional secretory pathways. Therefore, a broader perspective of mechanisms of secretion, as well as an appreciation for the ways in which the secretion of a wide range of different types of molecules can be regulated, will spawn new avenues of thought necessary to move us beyond the exosome-centric view that drives much of the current thinking of those who study of stem cell–mediated repair in the heart.  is what cells do; excretion is what the kidney does. Secretion is an active process by which cells release materials into the surrounding environment. Among the first secretion mechanisms studied were those involved in the regulated release of peptide hormones from endocrine cells. After release, substances can signal to cells afar via the blood stream (endocrine) and to neighboring cells (paracrine), as well as the cell of origin (autocrine). Additionally, some substances signal within the cell of origin (intracrine). Endocrine, paracrine, and autocrine signaling all involve the release of communicator substances directly into the interstitial spaces surrounding the cells of origin. Secretion into a duct, such as salivary or digestive enzyme secretion, is exocrine.Cells secrete many different substances, including proteins, lipids, steroids, nucleic acids, nucleotides, metabolites, and ions. Generally, these substances are secreted to facilitate communication with other cells and to affect the structure …

Expanding the Paracrine Hypothesis of Stem Cell–Mediated Repair in the Heart