No abstract

SUMMARY Arc is a cellular immediate early gene (IEG) that functions at excitatory synapses and is required for learning and memory. We report crystal structures of Arc subdomains that form a bi-lobar architecture remarkably similar to the capsid domain of human immunodeficiency virus (HIV) gag protein. Analysis indicates Arc originated from the Ty3/Gypsy retrotransposon family and was “domesticated” in higher vertebrates for synaptic functions. The Arc N-terminal lobe evolved a unique hydrophobic pocket that mediates intermolecular binding with synaptic proteins as resolved in complexes with TARPγ2 (Stargazin) and CaMKII peptides, and is essential for Arc’s synaptic function. A consensus sequence for Arc binding identifies several additional partners that include genes implicated in schizophrenia. Arc N-lobe binding is inhibited by small chemicals suggesting Arc’s synaptic action may be druggable. These studies reveal the remarkable evolutionary origin of Arc and provide a structural basis for understanding Arc’s contribution to neural plasticity and disease.

Exosomes are nano-sized vesicles that serve as mediators for cell-to-cell communication. With their unique nucleic acids, proteins, and lipids cargo compositions that reflect the characteristics of producer cells, exosomes can be utilized as cell-free therapeutics. Among exosomes derived from various cellular origins, mesenchymal stem cell-derived exosomes (MSC-exosomes) have gained great attention due to their immunomodulatory and regenerative functions. Indeed, many studies have shown anti-inflammatory, anti-aging and wound healing effects of MSC-exosomes in various in vitro and in vivo models. In addition, recent advances in the field of exosome biology have enabled development of specific guidelines and quality control methods, which will ultimately lead to clinical application of exosomes. This review highlights recent studies that investigate therapeutic potential of MSC-exosomes and relevant mode of actions for skin diseases, as well as quality control measures required for development of exosome-derived therapeutics.

Mesenchymal stem cell (MSC) transplantation is now considered as an effective treatment strategy for traumatic spinal cord injury (SCI). However, several key issues remain unresolved, including low survival rates, cell dedifferentiation, and tumor formation. Recent studies have demonstrated that the therapeutic effect of transplanted stem cells is primarily paracrine mediated. Exosomes are an important paracrine factor that can be used as a direct therapeutic agent. However, there are few reports on the application of exosomes derived from bone MSCs (BMSCs-Exos) in treating SCI. In this study, we demonstrated that BMSCs-Exos possessed robust proangiogenic properties, attenuated neuronal cells apoptosis, suppressed glial scar formation, attenuated lesion size, suppressed inflammation, promoted axonal regeneration, and eventually improved functional behavioral recovery effects after traumatic SCI. Briefly, lesion size was decreased by nearly 60%, neuronal apoptosis was attenuated by nearly 70%, glial scar formation was reduced by nearly 75%, average blood vessel density was increased by nearly 60%, and axonal regeneration was increased by almost 80% at day 28 after SCI in the BMSC-Exos group compared to the control group. Using a series of in vitro functional assays, we also confirmed that treatment with BSMCs-Exos significantly enhanced human umbilical vein endothelial cell proliferation, migration, and angiogenic tubule formation, attenuated neuronal cells apoptosis, and suppressed nitric oxide release in microglia. Moreover, our study demonstrated that administration of BMSCs-Exos suppressed inflammation efficiently after traumatic SCI and suppressed activation of A1 neurotoxic reactive astrocytes. In conclusion, our study suggested that the application of BMSCs-Exos may be a promising strategy for traumatic SCI.