International Journal of Molecular Sciences · 3 authors, 2 centres
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This review comprehensively examines non-classical intercellular communication mechanisms, including extracellular vesicles (exosomes and microvesicles) and membrane protrusions (cytonemes, tunneling nanotubes, and intercellular bridges). It highlights their critical roles in stem cell biology, oncogenesis, viral pathogenesis (including SARS-CoV-2), and regenerative medicine, emphasizing their therapeutic potential and the need for further mechanistic studies.
**Background:** Classical intercellular communication includes endocrine, paracrine, contact signaling, and nervous transmission. Over the past decade, non-classical mechanisms—extracellular vesicles (EVs) and membrane protrusions—have gained prominence. EVs, particularly exosomes (30–150 nm) and microvesicles (100–1000 nm), are secreted by diverse cell types and mediate intercellular transfer of proteins, lipids, and nucleic acids. Membrane protrusions such as cytonemes (closed-ended, actin-based, up to 700 μm) and tunneling nanotubes (TNTs; open- or closed-ended, actin-based, up to 250 μm) enable direct physical contact and transfer of organelles and pathogens. This review synthesizes current knowledge on the biogenesis, molecular composition, and biological roles of these non-classical communication modes, with emphasis on their implications in stem cell biology, oncogenesis, viral infection, and regenerative therapy.
**Methods:** This is a narrative review that synthesizes findings from primary research articles, preclinical studies, and meta-analyses published up to the time of writing. The authors conducted literature mining to cover key topics: EV biogenesis (including ESCRT-dependent and -independent pathways, ceramide-mediated mechanisms), EV roles in stem cell niches (e.g., hematopoietic stem cell quiescence, expansion, differentiation), EV involvement in oncogenesis (e.g., reprogramming of mesenchymal stem cells, modulation of immune microenvironment), EV applications in regenerative medicine (e.g., wound healing, neuroregeneration, anti-aging), and the roles of cytonemes and TNTs in morphogen signaling, pathogenesis (e.g., HIV, SARS-CoV-2, bacterial infections), and mitochondrial transfer for cellular repair. The review also discusses emerging concepts such as EV-mediated telomere donation and interorgan mitohermesis.
**Key Results:** Exosome biogenesis involves multivesicular body formation via ESCRT complexes, syndecan-syntenin-ALIX pathway, and lipid raft clustering. Mature exosomes are enriched in ceramides, cholesterol, and tetraspanins (CD9, CD63, CD81). MSC-derived EVs show therapeutic effects in chronic skin ulcers, acute lung injury (via keratinocyte growth factor mRNA), Alzheimer's disease (intraventricular administration improved behavioral performance), osteoarthritis (let-7e-5p miRNA targeting STAT3/IGF1R), and peripheral nerve regeneration (iPSC-derived exosomes with acellular nerve grafts). In COVID-19, EVs from allogeneic bone marrow MSCs (ExoFlo™) reversed hypoxia and suppressed cytokine storm in a non-randomized clinical study. EVs also mediate HSC niche regulation: MSC microvesicles contain Wnt and Hedgehog morphogens, and miR126-containing vesicles regulate HSC mobilization. In oncogenesis, tumor EVs transfer oncogenic NOTCH2 receptors, miR-155, and PD-1/PD-L1, reprogramming MSCs into pro-tumorigenic cells. Cytonemes facilitate morphogen transport (Wnt, Hedgehog, FGF) and are critical for asymmetric stem cell division. TNTs enable transfer of mitochondria, lysosomes, and pathogens; for example, MSCs transfer mitochondria to damaged corneal cells via TNTs (NF-κB/TNFαip2 pathway), and to macrophages to enhance antimicrobial activity in acute respiratory distress syndrome. TNT formation is induced by SARS-CoV-2 infection, HIV-1 Nef protein, and chemotherapeutic agents like 5-fluorouracil.
**Clinical Implications:** Non-classical intercellular communications offer promising therapeutic avenues. MSC-derived EVs avoid risks associated with direct stem cell transplantation (e.g., low survival, immune rejection) and show efficacy in preclinical models of tissue repair, neurodegeneration, and viral infection. Engineered EVs (e.g., with anti-CoV-2 nanobodies) represent novel targeted therapies. TNT-mediated mitochondrial transfer from MSCs to damaged cells (e.g., in kidney injury, corneal burns, intervertebral disc degeneration) suggests regenerative strategies. Inhibition of TNT formation (e.g., by cytochalasins, cytarabine) may block pathogen spread and chemoresistance. However, the complexity and heterogeneity of these mechanisms require further mechanistic studies to translate findings into clinical practice. The review underscores the need for standardized EV classification (MISEV guidelines) and highlights the potential of combining non-classical communication-based therapies with conventional treatments for improved outcomes.