Extracellular vesicles promote proliferation in an animal model of regeneration.

Extracellular vesicles (EVs) are secreted nanoparticles composed of a lipid bilayer that carry lipid, protein, and nucleic acid cargo between cells as a mode of intercellular communication. Although EVs can promote tissue repair in mammals, their roles in animals with greater regenerative capacity are not well understood. Planarian flatworms are capable of whole body regeneration due to pluripotent somatic stem cells called neoblasts that proliferate in response to injury. Here, using transmission electron microscopy, nanoparticle tracking analysis, and protein content examination, we showed that EVs enriched from the tissues of the planarian Schmidtea mediterranea had similar morphology and size as other eukaryotic EVs, and that these EVs carried orthologs of the conserved EV biogenesis regulators ALIX and TSG101. PKH67-labeled EVs were taken up more quickly by S/G2 neoblasts than G1 neoblasts/early progeny and differentiated cells. When injected into living planarians, EVs from regenerating tissue fragments enhanced upregulation of neoblast-associated transcripts. In addition, EV injection increased the number of F-ara-EdU-labelled cells by 49% as compared to buffer injection only. Our findings demonstrate that regenerating planarians produce EVs that promote stem cell proliferation, and suggest the planarian as an amenable in vivo model for the study of EV function during regeneration.

An Emerging Frontier in Intercellular Communication: Extracellular Vesicles in Regeneration.

Regeneration requires cellular proliferation, differentiation, and other processes that are regulated by secreted cues originating from cells in the local environment. Recent studies suggest that signaling by extracellular vesicles (EVs), another mode of paracrine communication, may also play a significant role in coordinating cellular behaviors during regeneration. EVs are nanoparticles composed of a lipid bilayer enclosing proteins, nucleic acids, lipids, and other metabolites, and are secreted by most cell types. Upon EV uptake by target cells, EV cargo can influence diverse cellular behaviors during regeneration, including cell survival, immune responses, extracellular matrix remodeling, proliferation, migration, and differentiation. In this review, we briefly introduce the history of EV research and EV biogenesis. Then, we review current understanding of how EVs regulate cellular behaviors during regeneration derived from numerous studies of stem cell-derived EVs in mammalian injury models. Finally, we discuss the potential of other established and emerging research organisms to expand our mechanistic knowledge of basic EV biology, how injury modulates EV biogenesis, cellular sources of EVs in vivo, and the roles of EVs in organisms with greater regenerative capacity.

Kallistatin Attenuates Experimental Autoimmune Uveitis by Inhibiting Activation of T Cells.

Experimental autoimmune uveoretinitis (EAU) is a mouse model of human autoimmune uveitis. EAU spontaneously resolves and is marked by ocular autoantigen-specific regulatory immunity in the spleen. Kallikrein binding protein (KBP) or kallistatin is a serine proteinase inhibitor that inhibits angiogenesis and inflammation, but its role in autoimmune uveitis has not been explored. We report that T cells activation is inhibited and EAU is attenuated in human KBP (HKBP) mice with no significant difference in the Treg population that we previously identified both before and after recovery from EAU. Moreover, following EAU immunization HKBP mice have potent ocular autoantigen specific regulatory immunity that is functionally suppressive.