Time-dependent LPS exposure commands MSC immunoplasticity through TLR4 activation leading to opposite therapeutic outcome in EAE
Journal
Stem Cell Research & Therapy
ISSN
1757-6512
Date Issued
2020
Author(s)
Mónica Kurte
Ana María Vega-Letter
Patricia Luz-Crawford
Farida Djouad
Danièle Noël
Maroun Khoury
Type
Resource Types::text::journal::journal article
URL Institutional Repository
Abstract
<jats:title>Abstract</jats:title><jats:sec>
<jats:title>Background</jats:title>
<jats:p>Mesenchymal stem cells (MSCs) have been recognized for their regenerative and anti-inflammatory capacity which makes them very attractive to cell therapy, especially those ones to treat inflammatory and autoimmune disease. Two different immune-phenotypes have been described for MSCs depending on which Toll-like receptor (TLR) is activated. MSC1 is endowed with a pro-inflammatory phenotype following TLR4 activation with LPS. On the other hand, anti-inflammatory MSC2 is induced by the activation of TLR3 with Poly(I:C). High immunoplasticity of MSCs is a matter of concern in cell-based therapies. In this study, we investigated whether a single stimulus can induce both types of MSCs through a differential activation of TLR4 with LPS.</jats:p>
</jats:sec><jats:sec>
<jats:title>Methods</jats:title>
<jats:p>MSCs were activated with LPS following a short exposure of 1-h (MSCs-LPS1h) or long-time exposure for 48 h (MSCs-LPS48h), and then, we evaluated the biological response in vitro, the immunosuppressive capacity of MSCs in vitro, and the therapeutic potential of MSCs in an experimental autoimmune encephalomyelitis (EAE) mouse model.</jats:p>
</jats:sec><jats:sec>
<jats:title>Results</jats:title>
<jats:p>Our results showed that 1-h LPS exposure induced a MSC1 phenotype. Indeed, MSCs-LPS1h expressed low levels of NO/iNOS and decreased immunosuppressive capacity in vitro without therapeutic effect in the EAE model. In contrast, MSCs-LPS48h achieved a MSC2-like phenotype with significant increase in the immunosuppressive capacity on T cell proliferation in vitro, together with an improved in the therapeutic effect and higher Treg, compared to unstimulated MSCs. Furthermore, we determine through the MSCs-TLR4KO that the expression of TLR4 receptor is essential for MSCs’ suppressive activity since TLR4 deletion was associated with a diminished suppressive effect in vitro and a loss of therapeutic effect in vivo.</jats:p>
</jats:sec><jats:sec>
<jats:title>Conclusions</jats:title>
<jats:p>We demonstrate that MSCs display a high immunoplasticity commanded by a single stimulus, where LPS exposure time regulated the MSC suppressive effect leading into either an enhanced or an impairment therapeutic activity. Our results underscore the importance of phenotype conversion probably related to the TLR4 expression and activation, in the design of future clinical protocols to treat patients with inflammatory and autoimmune diseases.</jats:p>
</jats:sec>
<jats:title>Background</jats:title>
<jats:p>Mesenchymal stem cells (MSCs) have been recognized for their regenerative and anti-inflammatory capacity which makes them very attractive to cell therapy, especially those ones to treat inflammatory and autoimmune disease. Two different immune-phenotypes have been described for MSCs depending on which Toll-like receptor (TLR) is activated. MSC1 is endowed with a pro-inflammatory phenotype following TLR4 activation with LPS. On the other hand, anti-inflammatory MSC2 is induced by the activation of TLR3 with Poly(I:C). High immunoplasticity of MSCs is a matter of concern in cell-based therapies. In this study, we investigated whether a single stimulus can induce both types of MSCs through a differential activation of TLR4 with LPS.</jats:p>
</jats:sec><jats:sec>
<jats:title>Methods</jats:title>
<jats:p>MSCs were activated with LPS following a short exposure of 1-h (MSCs-LPS1h) or long-time exposure for 48 h (MSCs-LPS48h), and then, we evaluated the biological response in vitro, the immunosuppressive capacity of MSCs in vitro, and the therapeutic potential of MSCs in an experimental autoimmune encephalomyelitis (EAE) mouse model.</jats:p>
</jats:sec><jats:sec>
<jats:title>Results</jats:title>
<jats:p>Our results showed that 1-h LPS exposure induced a MSC1 phenotype. Indeed, MSCs-LPS1h expressed low levels of NO/iNOS and decreased immunosuppressive capacity in vitro without therapeutic effect in the EAE model. In contrast, MSCs-LPS48h achieved a MSC2-like phenotype with significant increase in the immunosuppressive capacity on T cell proliferation in vitro, together with an improved in the therapeutic effect and higher Treg, compared to unstimulated MSCs. Furthermore, we determine through the MSCs-TLR4KO that the expression of TLR4 receptor is essential for MSCs’ suppressive activity since TLR4 deletion was associated with a diminished suppressive effect in vitro and a loss of therapeutic effect in vivo.</jats:p>
</jats:sec><jats:sec>
<jats:title>Conclusions</jats:title>
<jats:p>We demonstrate that MSCs display a high immunoplasticity commanded by a single stimulus, where LPS exposure time regulated the MSC suppressive effect leading into either an enhanced or an impairment therapeutic activity. Our results underscore the importance of phenotype conversion probably related to the TLR4 expression and activation, in the design of future clinical protocols to treat patients with inflammatory and autoimmune diseases.</jats:p>
</jats:sec>
Cite this document
Kurte, M., Vega-Letter, A. M., Luz-Crawford, P., Djouad, F., Noël, D., Khoury, M., & Carrión, F. (2020). Time-dependent LPS exposure commands MSC immunoplasticity through TLR4 activation leading to opposite therapeutic outcome in EAE. Stem Cell Research & Therapy, 11(1), 416. https://doi.org/10.1186/s13287-020-01840-2
Subjects
autoimmune diseases
;
cell plasticity
;
immunosuppression
;
lps
;
mscs
;
tlr4
;
animals
;
encephalomyelitis, autoimmune, experimental
;
humans
;
lipopolysaccharides
;
mesenchymal stem cells
;
mice
;
toll-like receptor 4
;
treatment outcome
;
inducible nitric oxide synthase
;
interleukin 6
;
lipopolysaccharide
;
nitric oxide
;
toll like receptor 4
;
lipopolysaccharide
;
tlr4 protein, human
;
tlr4 protein, mouse
;
toll like receptor 4
;
animal cell
;
animal experiment
;
animal model
;
animal tissue
;
article
;
cell activation
;
cell plasticity
;
controlled study
;
experimental autoimmune encephalomyelitis
;
female
;
in vitro study
;
in vivo study
;
lymphocyte differentiation
;
lymphocyte proliferation
;
mesenchymal stem cell
;
mesenchymal stem cell transplantation
;
mouse
;
nonhuman
;
priority journal
;
protein expression
;
regulatory t lymphocyte
;
t lymphocyte
;
th1 cell
;
th17 cell
;
therapy effect
;
treatment outcome
;
animal
;
genetics
;
human