Paracrine and extracellular vesicle-mediated signaling

Paracrine and extracellular vesicle-mediated signaling represents a multifaceted therapeutic mechanism where the primary mode of action is the secretion of bioactive molecules rather than direct cell-to-cell contact or a single drug-receptor interaction. This secretome includes a diverse array of cytokines, chemokines, and growth factors, as well as extracellular vesicles (EVs) such as exosomes and microvesicles that transport proteins, lipids, and genetic material (Gnecchi et al., 2008). In clinical contexts, particularly with mesenchymal stem cell (MSC) therapies, this mechanism is responsible for immunomodulation, angiogenesis, and tissue regeneration (Wiklander et al., 2015). Because the therapeutic effect is derived from the synergistic action of multiple components, identifying a single molecular target is often impossible, leading to its classification as an indirect or multiple-pathway mechanism in pharmacological databases. Challenges in this field include the standardization of EV characterization and the potential for pleiotropic effects that may vary across different physiological environments (Théry et al., 2018). Despite these challenges, targeting these pathways offers a holistic approach to treating complex diseases like heart failure, stroke, and autoimmune disorders.

Other names

Paracrine signalingExtracellular vesicle-mediated communicationSecretome-mediated effectsExosome-mediated signalingIndirect multiple pathways via paracrine factors and extracellular vesiclesCell-cell communication via secretome

The mechanism involves the release of a complex secretome consisting of soluble paracrine factors (e.g., TGF-beta, IL-10, VEGF) and membrane-bound extracellular vesicles that deliver functional cargo, including proteins and RNA, to target cells to alter their physiological state and promote tissue homeostasis (Gnecchi et al., 2008; Timmers et al., 2007).