Extracellular Vesicle (EV) Targeted Cells Release Secondary Effector EVs: Indication of How To Account for Histocompatibility and Disease Specificity of EV Treatments.

The central hypothesis presented here is that released extracellular vesicles (EVs) can act primarily on targeted cells to induce the production of secondary EVs to mediate the final biological events. Compared here are different instances. In one, EVs, primarily produced by CD8+ suppressor T cells, are activated in immune tolerance. These EVs transfer to companion recipient macrophages (Macs) the ability to generate production of secondary inhibitory EVs that affect the final-acting effector T cells. In a second instance of treating spinal cord injury (SCI), primary-acting mesenchymal stromal cell (MSC)-derived EVs target local tissue M2-type Macs to release secondary EVs that subsequently affect the local neuro microvasculature to mediate healing. Thus, these are very different systems acting similarly in this way. Per treatments with Mesenchymal Stromal Cells (MSCs), our proposal explains how their released EVs can act across tissue histocompatibility barriers and exhibit a seeming "disease specificity," resulting in the healing of many diverse injuries and a wide variety of pathologic conditions. It is postulated that the recipients of the primary EVs, the secondarily acting cells, are often but not exclusively Macs. These are among the local responding secondary-acting cells that produce transplantation-matched EVs. Further, the secondary-acting MSC-derived primary EVs that are clinically active in many diverse instances led to the additional hypothesis that secondary EVs produced by targeted local cells may be appropriate to each specific instance to explain such disease specificity. We propose that there may be many other examples to be uncovered in which primary EVs similarly induce secondary EV healing effects.