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Page 52 Extracell Vesicles Circ Nucleic Acids 2020;1:20-56 I http://dx.doi.org/10.20517/evcna.2020.10

liver, joints, heart and brain. A central question to discriminating between association and causality is, how
do gut microbes communicate with their host to affect physiological changes at the cellular and organ level
within the gut and beyond? We have uncovered roles for microbiota-derived metabolites and highly stable,
nanosized microvesicles (bacterial extracellular vesicles; BEVs) naturally produced in the gut by prominent
members of the intestinal microbiota in cross-kingdom communication. We have shown that specific
bacteria and their metabolites can affect various sensory cells of the immune, endocrine and nervous
systems within the intestinal mucosa and that BEVs can bring about changes in host cell physiology by
delivering various cargo including metabolic enzymes and mediators of intracellular signaling. Via their
ability to cross the intestinal and respiratory epithelium and access the lymphatic and vascular system
they can activate innate and adaptive immune cells locally and throughout the body to promote local and
systemic regulatory immune responses. Furthermore, we have exploited this BEV-mediated cross-kingdom
communication pathway to develop a biologics delivery technology platform using BEVs to deliver
therapeutic proteins and vaccine antigens directly to mucosal tissues. Pre-clinical studies highlight the
utility of this technology in both boosting natural immunity and in preventing and treating infection and
autoimmune mediated pathologies that affect the gut and lungs, and other tissues.

43. Infectious Exosomes/Microvesicles in Degenerative and Neoplastic Stem Cell Pathologies

Authors: Dennis A. Steindler
E-mail: stemcellguy@gmail.com
Affiliations:
The UNC Eshelman School of Pharmacy and Institute for Innovation, the University of North Carolina Chapel
Hill, Chapel Hill, NC, USA.
Steindler Consulting, Boston, FA, USA.

Abstracts: The role of exosomes/microvesicles (“EMVs”) in cell-cell communication is important in
understanding infectious-like transmission of disease in everything from COVID-19 to Parkinson’s and
[1]
cancer. Our previous studies have linked infectious disease to neurodegenerative diseases and cancer ,
where stem cells have been shown to have a vulnerability to EMV conveyance of disease-associated
[2,3]
nucleic acids and proteins . We also showed that lectins, toxins and viruses have the ability to bind
[4]
to particular glycoconjugates on the surfaces of stem and differentiated neural cells, and transcellularly
transport to distant central nervous system (“CNS”) sites. This hijacking of the neural connectome leads
to stem cell pathologies where not enough differentiated progeny are generated and potentially contribute
to neurodegenerative disease, or, on the contrary, lead to too many progeny being generated as in the
[5,6]
case of glioblastoma , where the transcellular transport of such potentially infectious EMV molecular
[7]
cargoes may underlie gliomagenesis and spread . We have been studying such an infectious nature of
Parkinson’s disease by way of characterizing stem cell EMVs from normal, idiopathic, gene-identified (e.g.,
LRRK2 G2019S mutant) and gene-corrected Parkinson’s Disease patients using Nanosight technology,
immunocytochemistry and gene expression profiling to identify at-risk networks involved in the initiation
and propagation of disease. We have identified EMV-associated genes including SOD1, SOD2, HIF1a,
APP, JAK2 and GSK3B involved in both stem cell behavior and neurodegeneration, and furthermore
showed that LRRK2 gene correction altered the molecular profile of EMVs to a near normal expression
pattern as seen in control iPSC-derived dopamine neuron EMVs. Knowing the cell and molecular bases
for route of entry and system to system transmission of pathogenic elements will help us to better design
precision therapies that can target particular virus-cell, cell-cell and multisystem interactions underlying
standard brain versus disease-associated neural functions. For example, the highly pathogenic H5N1 virus
[8]
has been shown to enter the CNS , potentially from peripheral, e.g., vagus nerve innervation of primary