Toll-like receptor 4 modulation influences human neural stem cell proliferation and differentiation article

Chiara Grasselli, Daniela Ferrari, Cristina Zalfa, Matias Soncini, Gianluigi Mazzoccoli, Fabio A. Facchini, Laura Marongiu, Francesca Granucci, Massimiliano Copetti, Angelo Luigi Vescovi, Francesco Peri, Lidia De Filippis

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Toll-like receptor 4 (TLR4) activation is pivotal to innate immunity and has been shown to regulate proliferation and differentiation of human neural stem cells (hNSCs) in vivo. Here we study the role of TLR4 in regulating hNSC derived from the human telencephalic-diencephalic area of the fetal brain and cultured in vitro as neurospheres in compliance with Good Manifacture Procedures (GMP) guidelines. Similar batches have been used in recent clinical trials in ALS patients. We found that TLR2 and 4 are expressed in hNSCs as well as CD14 and MD-2 co-receptors, and TLR4 expression is downregulated upon differentiation. Activation of TLR4 signaling by lipopolysaccharide (LPS) has a positive effect on proliferation and/or survival while the inverse is observed with TLR4 inhibition by a synthetic antagonist. TLR4 activation promotes neuronal and oligodendrocyte differentiation and/or survival while TLR4 inhibition leads to increased apoptosis. Consistently, endogenous expression of TLR4 is retained by hNSC surviving after transplantation in ALS rats or immunocompromised mice, thus irrespectively of the neuroinflammatory environment. The characterization of downstream signaling of TLR4 in hNSCs has suggested some activation of the inflammasome pathway. This study suggests TLR4 signaling as essential for hNSC self-renewal and as a novel target for the study of neurogenetic mechanisms.

Original languageEnglish
Article number280
JournalCell Death and Disease
Volume9
Issue number3
DOIs
Publication statusPublished - Mar 1 2018

Fingerprint

Toll-Like Receptor 4
Neural Stem Cells
Cell Differentiation
Cell Proliferation
Inflammasomes
Telencephalon
Survival
Oligodendroglia
Innate Immunity
Lipopolysaccharides
Down-Regulation
Transplantation
Clinical Trials
Guidelines
Apoptosis

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Toll-like receptor 4 modulation influences human neural stem cell proliferation and differentiation article. / Grasselli, Chiara; Ferrari, Daniela; Zalfa, Cristina; Soncini, Matias; Mazzoccoli, Gianluigi; Facchini, Fabio A.; Marongiu, Laura; Granucci, Francesca; Copetti, Massimiliano; Vescovi, Angelo Luigi; Peri, Francesco; De Filippis, Lidia.

In: Cell Death and Disease, Vol. 9, No. 3, 280, 01.03.2018.

Research output: Contribution to journalArticle

Grasselli, Chiara ; Ferrari, Daniela ; Zalfa, Cristina ; Soncini, Matias ; Mazzoccoli, Gianluigi ; Facchini, Fabio A. ; Marongiu, Laura ; Granucci, Francesca ; Copetti, Massimiliano ; Vescovi, Angelo Luigi ; Peri, Francesco ; De Filippis, Lidia. / Toll-like receptor 4 modulation influences human neural stem cell proliferation and differentiation article. In: Cell Death and Disease. 2018 ; Vol. 9, No. 3.
@article{98f1231297a34d949ac87148babfc6a2,
title = "Toll-like receptor 4 modulation influences human neural stem cell proliferation and differentiation article",
abstract = "Toll-like receptor 4 (TLR4) activation is pivotal to innate immunity and has been shown to regulate proliferation and differentiation of human neural stem cells (hNSCs) in vivo. Here we study the role of TLR4 in regulating hNSC derived from the human telencephalic-diencephalic area of the fetal brain and cultured in vitro as neurospheres in compliance with Good Manifacture Procedures (GMP) guidelines. Similar batches have been used in recent clinical trials in ALS patients. We found that TLR2 and 4 are expressed in hNSCs as well as CD14 and MD-2 co-receptors, and TLR4 expression is downregulated upon differentiation. Activation of TLR4 signaling by lipopolysaccharide (LPS) has a positive effect on proliferation and/or survival while the inverse is observed with TLR4 inhibition by a synthetic antagonist. TLR4 activation promotes neuronal and oligodendrocyte differentiation and/or survival while TLR4 inhibition leads to increased apoptosis. Consistently, endogenous expression of TLR4 is retained by hNSC surviving after transplantation in ALS rats or immunocompromised mice, thus irrespectively of the neuroinflammatory environment. The characterization of downstream signaling of TLR4 in hNSCs has suggested some activation of the inflammasome pathway. This study suggests TLR4 signaling as essential for hNSC self-renewal and as a novel target for the study of neurogenetic mechanisms.",
author = "Chiara Grasselli and Daniela Ferrari and Cristina Zalfa and Matias Soncini and Gianluigi Mazzoccoli and Facchini, {Fabio A.} and Laura Marongiu and Francesca Granucci and Massimiliano Copetti and Vescovi, {Angelo Luigi} and Francesco Peri and {De Filippis}, Lidia",
year = "2018",
month = "3",
day = "1",
doi = "10.1038/s41419-017-0139-8",
language = "English",
volume = "9",
journal = "Cell Death and Disease",
issn = "2041-4889",
publisher = "Nature Publishing Group",
number = "3",

}

TY - JOUR

T1 - Toll-like receptor 4 modulation influences human neural stem cell proliferation and differentiation article

AU - Grasselli, Chiara

AU - Ferrari, Daniela

AU - Zalfa, Cristina

AU - Soncini, Matias

AU - Mazzoccoli, Gianluigi

AU - Facchini, Fabio A.

AU - Marongiu, Laura

AU - Granucci, Francesca

AU - Copetti, Massimiliano

AU - Vescovi, Angelo Luigi

AU - Peri, Francesco

AU - De Filippis, Lidia

PY - 2018/3/1

Y1 - 2018/3/1

N2 - Toll-like receptor 4 (TLR4) activation is pivotal to innate immunity and has been shown to regulate proliferation and differentiation of human neural stem cells (hNSCs) in vivo. Here we study the role of TLR4 in regulating hNSC derived from the human telencephalic-diencephalic area of the fetal brain and cultured in vitro as neurospheres in compliance with Good Manifacture Procedures (GMP) guidelines. Similar batches have been used in recent clinical trials in ALS patients. We found that TLR2 and 4 are expressed in hNSCs as well as CD14 and MD-2 co-receptors, and TLR4 expression is downregulated upon differentiation. Activation of TLR4 signaling by lipopolysaccharide (LPS) has a positive effect on proliferation and/or survival while the inverse is observed with TLR4 inhibition by a synthetic antagonist. TLR4 activation promotes neuronal and oligodendrocyte differentiation and/or survival while TLR4 inhibition leads to increased apoptosis. Consistently, endogenous expression of TLR4 is retained by hNSC surviving after transplantation in ALS rats or immunocompromised mice, thus irrespectively of the neuroinflammatory environment. The characterization of downstream signaling of TLR4 in hNSCs has suggested some activation of the inflammasome pathway. This study suggests TLR4 signaling as essential for hNSC self-renewal and as a novel target for the study of neurogenetic mechanisms.

AB - Toll-like receptor 4 (TLR4) activation is pivotal to innate immunity and has been shown to regulate proliferation and differentiation of human neural stem cells (hNSCs) in vivo. Here we study the role of TLR4 in regulating hNSC derived from the human telencephalic-diencephalic area of the fetal brain and cultured in vitro as neurospheres in compliance with Good Manifacture Procedures (GMP) guidelines. Similar batches have been used in recent clinical trials in ALS patients. We found that TLR2 and 4 are expressed in hNSCs as well as CD14 and MD-2 co-receptors, and TLR4 expression is downregulated upon differentiation. Activation of TLR4 signaling by lipopolysaccharide (LPS) has a positive effect on proliferation and/or survival while the inverse is observed with TLR4 inhibition by a synthetic antagonist. TLR4 activation promotes neuronal and oligodendrocyte differentiation and/or survival while TLR4 inhibition leads to increased apoptosis. Consistently, endogenous expression of TLR4 is retained by hNSC surviving after transplantation in ALS rats or immunocompromised mice, thus irrespectively of the neuroinflammatory environment. The characterization of downstream signaling of TLR4 in hNSCs has suggested some activation of the inflammasome pathway. This study suggests TLR4 signaling as essential for hNSC self-renewal and as a novel target for the study of neurogenetic mechanisms.

UR - http://www.scopus.com/inward/record.url?scp=85042199504&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85042199504&partnerID=8YFLogxK

U2 - 10.1038/s41419-017-0139-8

DO - 10.1038/s41419-017-0139-8

M3 - Article

AN - SCOPUS:85042199504

VL - 9

JO - Cell Death and Disease

JF - Cell Death and Disease

SN - 2041-4889

IS - 3

M1 - 280

ER -