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Choroid plexus extracellular vesicle transport of blood-borne insulin-like growth factor 1 to the hippocampus of the immature brain

Ortenlöf, Niklas LU ; Vallius, Suvi LU ; Karlsson, Helena LU ; Ekström, Claes LU orcid ; Kristiansson, Amanda LU ; Holmqvist, Bo LU ; Pankratova, Stanislava ; Barton, Norman ; Ley, David LU and Gram, Magnus LU orcid (2024) In PNAS Nexus 3(12).
Abstract

Reduced serum level of insulin-like growth factor 1 (IGF-1), a major regulator of perinatal development, in extremely preterm infants has been shown to be associated with neurodevelopmental impairment. To clarify the mechanism of IGF-1 transport at the blood–cerebrospinal fluid (CSF) barrier of the immature brain, we combined studies of in vivo preterm piglet and rabbit models with an in vitro transwell cell culture model of neonatal primary murine choroid plexus epithelial (ChPE) cells. We identified IGF-1-positive intracellular vesicles in ChPE cells and provided data indicating a directional transport of IGF-1 from the basolateral to the apical media in extracellular vesicles (EVs). Exposure of the ChPE cells to human IGF-1 on the... (More)

Reduced serum level of insulin-like growth factor 1 (IGF-1), a major regulator of perinatal development, in extremely preterm infants has been shown to be associated with neurodevelopmental impairment. To clarify the mechanism of IGF-1 transport at the blood–cerebrospinal fluid (CSF) barrier of the immature brain, we combined studies of in vivo preterm piglet and rabbit models with an in vitro transwell cell culture model of neonatal primary murine choroid plexus epithelial (ChPE) cells. We identified IGF-1-positive intracellular vesicles in ChPE cells and provided data indicating a directional transport of IGF-1 from the basolateral to the apical media in extracellular vesicles (EVs). Exposure of the ChPE cells to human IGF-1 on the basolateral side increased the secretion of IGF-1-positive EVs in the apical media. Mass spectrometry analysis displayed similarities in protein content between EVs derived from preterm piglet CSF-derived and ChPE cell–derived EVs. Furthermore, exposure of ChPE cells to human IGF-1 caused an enrichment of human IGF-1 and transmembrane p24 trafficking protein 2, proteins important for perinatal development, in apical media–derived EVs. Moreover, intraventricular injections of ChPE cell–derived EVs in preterm rabbit pups resulted in an uptake of EVs in the brain, displaying penetration through the ependymal lining and deep into the hippocampus. Finally, exposure of rat hippocampus neurons to ChPE cell–derived EVs resulted in internalization of the EVs in hippocampal soma and neurites. In summary, we describe a transport pathway for blood-borne IGF-1 in EVs through the blood–CSF barrier to the hippocampus in the immature brain.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
choroid plexus, extracellular vesicle, hippocampus, immature brain, insulin-like growth factor 1
in
PNAS Nexus
volume
3
issue
12
article number
pgae496
publisher
Oxford University Press
external identifiers
  • pmid:39660059
  • scopus:85211990486
ISSN
2752-6542
DOI
10.1093/pnasnexus/pgae496
language
English
LU publication?
yes
id
03207c51-53b4-4cef-935f-349d4d0991cb
date added to LUP
2025-01-20 12:57:47
date last changed
2025-07-08 02:29:46
@article{03207c51-53b4-4cef-935f-349d4d0991cb,
  abstract     = {{<p>Reduced serum level of insulin-like growth factor 1 (IGF-1), a major regulator of perinatal development, in extremely preterm infants has been shown to be associated with neurodevelopmental impairment. To clarify the mechanism of IGF-1 transport at the blood–cerebrospinal fluid (CSF) barrier of the immature brain, we combined studies of in vivo preterm piglet and rabbit models with an in vitro transwell cell culture model of neonatal primary murine choroid plexus epithelial (ChPE) cells. We identified IGF-1-positive intracellular vesicles in ChPE cells and provided data indicating a directional transport of IGF-1 from the basolateral to the apical media in extracellular vesicles (EVs). Exposure of the ChPE cells to human IGF-1 on the basolateral side increased the secretion of IGF-1-positive EVs in the apical media. Mass spectrometry analysis displayed similarities in protein content between EVs derived from preterm piglet CSF-derived and ChPE cell–derived EVs. Furthermore, exposure of ChPE cells to human IGF-1 caused an enrichment of human IGF-1 and transmembrane p24 trafficking protein 2, proteins important for perinatal development, in apical media–derived EVs. Moreover, intraventricular injections of ChPE cell–derived EVs in preterm rabbit pups resulted in an uptake of EVs in the brain, displaying penetration through the ependymal lining and deep into the hippocampus. Finally, exposure of rat hippocampus neurons to ChPE cell–derived EVs resulted in internalization of the EVs in hippocampal soma and neurites. In summary, we describe a transport pathway for blood-borne IGF-1 in EVs through the blood–CSF barrier to the hippocampus in the immature brain.</p>}},
  author       = {{Ortenlöf, Niklas and Vallius, Suvi and Karlsson, Helena and Ekström, Claes and Kristiansson, Amanda and Holmqvist, Bo and Pankratova, Stanislava and Barton, Norman and Ley, David and Gram, Magnus}},
  issn         = {{2752-6542}},
  keywords     = {{choroid plexus; extracellular vesicle; hippocampus; immature brain; insulin-like growth factor 1}},
  language     = {{eng}},
  number       = {{12}},
  publisher    = {{Oxford University Press}},
  series       = {{PNAS Nexus}},
  title        = {{Choroid plexus extracellular vesicle transport of blood-borne insulin-like growth factor 1 to the hippocampus of the immature brain}},
  url          = {{http://dx.doi.org/10.1093/pnasnexus/pgae496}},
  doi          = {{10.1093/pnasnexus/pgae496}},
  volume       = {{3}},
  year         = {{2024}},
}