Page 121 - Read Online

Page 241 Raposo et al. Extracell Vesicles Circ Nucleic Acids 2023;4:240-54 https://dx.doi.org/10.20517/evcna.2023.18

Keywords: Extracellular vesicles, biogenesis, intercellular communication, endocrine, homeostasis

INTRODUCTION
A series of recent Nobel Prizes bookends the rapid progress in cell biology leading to our understanding of
the biogenesis of extracellular vesicles and their promising but still uncharted role in human biology
including medicine and plant science. Christian de Duve, who received the Prize for his discovery of the
lysosome, speculated on the movement of materials into and out of cells in his depiction of a concept called
exoplasmic space . Exoplasmic space in eukaryotic cells is seen as an intracellular vacuolar space that is in
[1]
immediate contact with extracellular space. At this interface, cells could both receive and discharge all
manner of things. De Duve was aware of the role of cellular housekeeping in disease, and his early work led
to the understanding of lysosomal storage diseases such as Pompe’s disease, in which cells cannot degrade
[2]
glycogen and accumulate it within membrane-bound vesicles . De Duve used the descriptor cellular
defecation to describe a process where cells could rid themselves of unwanted material trapped within
vesicular compartments, a problem of broad contemporary interest in studies of neurodegenerative and
other diseases. The 1985 Nobel Prize to Joseph L. Goldstein and Michael S. Brown highlighted their work
[3]
on cholesterol metabolism and focused on the mechanisms by which LDL particles entered cells . A key
finding was the discovery that signals are encoded in the cytoplasmic tails of receptors that engage a
previously unknown sorting machinery that guides internalized receptors to their destination. Brown and
Goldstein’s work and that of many others was a harbinger for the rise of a molecular understanding of
membrane trafficking as we know it today. The molecular toolbox that opened a pathway to a broader
understanding of membrane trafficking took advantage of the “awesome power of yeast genetics “and the
work of Randy Schekman and his scientific offspring . Schekman’s Nobel Prize was awarded for his
[4]
pioneering work on the genetic control of membrane trafficking that, like most Nobel Prizes, opened the
gates of opportunity for generations of researchers, biological and biomedical. Now the challenge for the
next generation is to build on these many accomplishments to develop or extend membrane trafficking
models from intracellular to extracellular - how do cells use membrane trafficking pathways to allow cells
and tissues to communicate with each other and how does this new understanding translate to diagnostics
and therapeutics. What remains is a challenge for a new generation that will have a significant impact on
our understanding of the human condition.

DISCOVERED BY SERENDIPITY, EVS HAVE EVOLVED AS A PART OF A LARGER
COMMUNICATION AND REGULATORY SYSTEM IN METAZOANS
Unlike most major discoveries in the biological sciences, the discovery of EVs as players in cell
communication was revealed by serendipity and documented by careful follow-up research . Now
[5]
confirmed by many, the finding was revolutionary; vesicles released by one cell can deliver informational
content to a second cell. Because the concept was new and not broadly tested and basically anathema to
funding agencies, time was needed to broaden the concept. Over the past three decades, much has been
accomplished and the concept is now widely accepted in scientific circles. The pathway from discovery to
application is a long journey for most discoveries and longer for discoveries that break with commonly held
views. Such is the case with EV-based signaling.

Cells from all three domains of life, Archaea, Bacteria and Eukarya, produce extracellular vesicles. In
metazoans and multicellular plants, Extracellular Vesicle (EV)-based signaling allows cells to communicate
with each other independently of cell-cell contact at short and long distances with different outcomes in
tissue homeostasis and in disease . Extracellular Vesicles released from the plasma membrane
[6,7]
(microvesicles or ectosomes) and the endo-lysosomal system (exosomes) can be viewed as “miniature cells”