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

Niklas Ortenlöf; Suvi Vallius; Helena Karlsson; Claes Ekström; Amanda Kristiansson; Bo Holmqvist; Stanislava Pankratova; Norman Barton; David Ley; Magnus Gram

doi:10.1093/pnasnexus/pgae496

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

Niklas Ortenlöf
, Suvi Vallius
, Helena Karlsson
, Claes Ekström
, Amanda Kristiansson
, Bo Holmqvist
, Stanislava Pankratova
, Norman Barton
, David Ley
, Magnus Gram^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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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 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.

Originalsprog	Engelsk
Artikelnummer	pgae496
Tidsskrift	PNAS Nexus
Vol/bind	3
Udgave nummer	12
Antal sider	14
ISSN	2752-6542
DOI	https://doi.org/10.1093/pnasnexus/pgae496
Status	Udgivet - 2024

Bibliografisk note

Funding Information:
The authors acknowledge Lina Gefors and Sebastian Wasserstr\u00F6m, Lund University Bioimaging Center, for providing technical assistance and scientific support related to the TEM and confocal microscopy. In addition, the authors acknowledge Charlotte Welinder, Center of Excellence in Biological and Medical Mass Spectrometry at Lund University, for conducting the MS experiments. The authors also acknowledge Anders Brinte for providing assistance in the fluorescence analysis and Pia Ecke, Imagene-iT AB, for histological work related to the confocal microscopy analyses. The research was funded by the Swedish Research Council (Grant No. 2020-01235), Governmental ALF research grants to Lund University and Sk\u00E5ne University Hospital, the Crafoord Foundation, the Alfred \u00D6sterlund Foundation, and Takeda Pharmaceutical Company Ltd.

Funding Information:
The research was funded by the Swedish Research Council (Grant No. 2020-01235), Governmental ALF research grants to Lund University and Sk\u00E5ne University Hospital, the Crafoord Foundation, the Alfred \u00D6sterlund Foundation, and Takeda Pharmaceutical Company Ltd.

Publisher Copyright:
© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.

Finansiering

The authors acknowledge Lina Gefors and Sebastian Wasserstr\u00F6m, Lund University Bioimaging Center, for providing technical assistance and scientific support related to the TEM and confocal microscopy. In addition, the authors acknowledge Charlotte Welinder, Center of Excellence in Biological and Medical Mass Spectrometry at Lund University, for conducting the MS experiments. The authors also acknowledge Anders Brinte for providing assistance in the fluorescence analysis and Pia Ecke, Imagene-iT AB, for histological work related to the confocal microscopy analyses. The research was funded by the Swedish Research Council (Grant No. 2020-01235), Governmental ALF research grants to Lund University and Sk\u00E5ne University Hospital, the Crafoord Foundation, the Alfred \u00D6sterlund Foundation, and Takeda Pharmaceutical Company Ltd. The research was funded by the Swedish Research Council (Grant No. 2020-01235), Governmental ALF research grants to Lund University and Sk\u00E5ne University Hospital, the Crafoord Foundation, the Alfred \u00D6sterlund Foundation, and Takeda Pharmaceutical Company Ltd.

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Citationsformater

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

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{\textendash}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{\textendash}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{\textendash}derived EVs. Moreover, intraventricular injections of ChPE cell{\textendash}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{\textendash}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{\textendash}CSF barrier to the hippocampus in the immature brain.",

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author = "Niklas Ortenl{\"o}f and Suvi Vallius and Helena Karlsson and Claes Ekstr{\"o}m and Amanda Kristiansson and Bo Holmqvist and Stanislava Pankratova and Norman Barton and David Ley and Magnus Gram",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.",

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T1 - Choroid plexus extracellular vesicle transport of blood-borne insulin-like growth factor 1 to the hippocampus of the immature brain

AU - Ortenlöf, Niklas

AU - Vallius, Suvi

AU - Karlsson, Helena

AU - Ekström, Claes

AU - Kristiansson, Amanda

AU - Holmqvist, Bo

AU - Pankratova, Stanislava

AU - Barton, Norman

AU - Ley, David

AU - Gram, Magnus

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

KW - choroid plexus

KW - extracellular vesicle

KW - hippocampus

KW - immature brain

KW - insulin-like growth factor 1

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DO - 10.1093/pnasnexus/pgae496

M3 - Journal article

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SN - 2752-6542

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JO - PNAS Nexus

JF - PNAS Nexus

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M1 - pgae496

ER -