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Loh et al. Extracell Vesicles Circ Nucleic Acids 2023;4:568-87 Extracellular Vesicles and
DOI: 10.20517/evcna.2023.34
Circulating Nucleic Acids

Review Open Access

Trafficking of hormones and trophic factors to
secretory and extracellular vesicles: a historical

perspective and new hypothesis

1
1
Y. Peng Loh , Lan Xiao , Joshua J. Park 2
1
Section on Cellular Neurobiology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National
Institutes of Health, Bethesda, MD 20892, USA.
2
Scientific Review Branch, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
Correspondence to: Dr. Y. Peng Loh, Section on Cellular Neurobiology, Eunice Kennedy Shriver National Institute of Child Health
and Human Development, National Institutes of Health, 49, Convent Drive, Bldg 49, Rm 6A-10, Bethesda, MD 20892, USA. E-
mail: lohp@mail.nih.gov; Dr. Joshua J. Park, Scientific Review Branch, National Institute on Aging, National Institutes of Health,
31, Center Drive, Bldg 31C, Bethesda, MD 20892, USA. E-mail: joshua.park4@nih.gov

How to cite this article: Loh YP, Xiao L, Park JJ. Trafficking of hormones and trophic factors to secretory and extracellular
vesicles: a historical perspective and new hypothesis. Extracell Vesicles Circ Nucleic Acids 2023;4:568-87. https://dx.doi.org/10.
20517/evcna.2023.34
Received: 30 Jun 2023 First Decision: 15 Aug 2023 Revised: 17 Oct 2023 Accepted: 2 Nov 2023 Published: 10 Nov 2023

Academic Editors: Frank R.M. Stassen, Michael Graner Copy Editor: Dan Zhang Production Editor: Dan Zhang

Abstract
It is well known that peptide hormones and neurotrophic factors are intercellular messengers that are packaged
into secretory vesicles in endocrine cells and neurons and released by exocytosis upon the stimulation of the cells
in a calcium-dependent manner. These secreted molecules bind to membrane receptors, which then activate signal
transduction pathways to mediate various endocrine/trophic functions. Recently, there is evidence that these
molecules are also in extracellular vesicles, including small extracellular vesicles (sEVs), which appear to be taken
up by recipient cells. This finding raised the hypothesis that they may have functions differentiated from their
classical secretory hormone/neurotrophic factor actions. In this article, the historical perspective and updated
mechanisms for the sorting and packaging of hormones and neurotrophic factors into secretory vesicles and their
transport in these organelles for release at the plasma membrane are reviewed. In contrast, little is known about
the packaging of hormones and neurotrophic factors into extracellular vesicles. One proposal is that these
molecules could be sorted at the trans-Golgi network, which then buds to form Golgi-derived vesicles that can fuse
to endosomes and subsequently form intraluminal vesicles. They are then taken up by multivesicular bodies to
form extracellular vesicles, which are subsequently released. Other possible mechanisms for packaging RSP
proteins into sEVs are discussed. We highlight some studies in the literature that suggest the dual vesicular

© 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International
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