Altered Immunomodulatory Responses in the CX3CL1/CX3CR1 Axis Mediated by hMSCs in an Early In Vitro SOD1<sup>G93A</sup> Model of ALS

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron (MN) disease characterized by progressive MN loss and muscular atrophy resulting in rapidly progressive paralysis and respiratory failure. Human mesenchymal stem/stromal cell (hMSC)-based therapy has been suggested to prolong MN survival vi...

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Main Authors: Anastasia Sarikidi, Ekaterini Kefalakes, Christine S. Falk, Ruth Esser, Arnold Ganser, Nadine Thau-Habermann, Susanne Petri
Format: Article
Language:English
Published: MDPI AG 2022-11-01
Series:Biomedicines
Subjects:
Online Access:https://www.mdpi.com/2227-9059/10/11/2916
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author Anastasia Sarikidi
Ekaterini Kefalakes
Christine S. Falk
Ruth Esser
Arnold Ganser
Nadine Thau-Habermann
Susanne Petri
author_facet Anastasia Sarikidi
Ekaterini Kefalakes
Christine S. Falk
Ruth Esser
Arnold Ganser
Nadine Thau-Habermann
Susanne Petri
author_sort Anastasia Sarikidi
collection DOAJ
description Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron (MN) disease characterized by progressive MN loss and muscular atrophy resulting in rapidly progressive paralysis and respiratory failure. Human mesenchymal stem/stromal cell (hMSC)-based therapy has been suggested to prolong MN survival via secretion of growth factors and modulation of cytokines/chemokines. We investigated the effects of hMSCs and a hMSC-conditioned medium (CM) on Cu/Zn superoxidase dismutase 1<sup>G93A</sup> (SOD1<sup>G93A</sup>) transgenic primary MNs. We found that co-culture of hMSCs and MNs resulted in slightly higher MN numbers, but did not protect against staurosporine (STS)-induced toxicity, implying marginal direct trophic effects of hMSCs. Aiming to elucidate the crosstalk between hMSCs and MNs in vitro, we found high levels of vascular endothelial growth factor (VEGF) and C-X3-C motif chemokine 1 (CX3CL1) in the hMSC secretome. Co-culture of hMSCs and MNs resulted in altered gene expression of growth factors and cytokines/chemokines in both MNs and hMSCs. hMSCs showed upregulation of CX3CL1 and its receptor CX3CR1 and downregulation of interleukin-1 β (IL1β) and interleukin-8 (IL8) when co-cultured with SOD1<sup>G93A</sup> MNs. MNs, on the other hand, showed upregulation of growth factors as well as CX3CR1 upon hMSC co-culture. Our results indicate that hMSCs only provide moderate trophic support to MNs by growth factor gene regulation and may mediate anti-inflammatory responses through the CX3CL1/CX3CR1 axis, but also increase expression of pro-inflammatory cytokines, which limits their therapeutic potential.
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spelling doaj.art-929dcc5a9eb54567a26a3eb773b0793b2023-11-24T07:46:09ZengMDPI AGBiomedicines2227-90592022-11-011011291610.3390/biomedicines10112916Altered Immunomodulatory Responses in the CX3CL1/CX3CR1 Axis Mediated by hMSCs in an Early In Vitro SOD1<sup>G93A</sup> Model of ALSAnastasia Sarikidi0Ekaterini Kefalakes1Christine S. Falk2Ruth Esser3Arnold Ganser4Nadine Thau-Habermann5Susanne Petri6Department of Neurology, Hannover Medical School, 30625 Hannover, GermanyDepartment of Neurology, Hannover Medical School, 30625 Hannover, GermanyInstitute of Transplant Immunology, Hannover Medical School, 30625 Hannover, GermanyInstitute of Cellular Therapeutics, Hannover Medical School, 30625 Hannover, GermanyInstitute of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, GermanyDepartment of Neurology, Hannover Medical School, 30625 Hannover, GermanyDepartment of Neurology, Hannover Medical School, 30625 Hannover, GermanyAmyotrophic lateral sclerosis (ALS) is a fatal motor neuron (MN) disease characterized by progressive MN loss and muscular atrophy resulting in rapidly progressive paralysis and respiratory failure. Human mesenchymal stem/stromal cell (hMSC)-based therapy has been suggested to prolong MN survival via secretion of growth factors and modulation of cytokines/chemokines. We investigated the effects of hMSCs and a hMSC-conditioned medium (CM) on Cu/Zn superoxidase dismutase 1<sup>G93A</sup> (SOD1<sup>G93A</sup>) transgenic primary MNs. We found that co-culture of hMSCs and MNs resulted in slightly higher MN numbers, but did not protect against staurosporine (STS)-induced toxicity, implying marginal direct trophic effects of hMSCs. Aiming to elucidate the crosstalk between hMSCs and MNs in vitro, we found high levels of vascular endothelial growth factor (VEGF) and C-X3-C motif chemokine 1 (CX3CL1) in the hMSC secretome. Co-culture of hMSCs and MNs resulted in altered gene expression of growth factors and cytokines/chemokines in both MNs and hMSCs. hMSCs showed upregulation of CX3CL1 and its receptor CX3CR1 and downregulation of interleukin-1 β (IL1β) and interleukin-8 (IL8) when co-cultured with SOD1<sup>G93A</sup> MNs. MNs, on the other hand, showed upregulation of growth factors as well as CX3CR1 upon hMSC co-culture. Our results indicate that hMSCs only provide moderate trophic support to MNs by growth factor gene regulation and may mediate anti-inflammatory responses through the CX3CL1/CX3CR1 axis, but also increase expression of pro-inflammatory cytokines, which limits their therapeutic potential.https://www.mdpi.com/2227-9059/10/11/2916amyotrophic lateral sclerosisSOD1<sup>G93A</sup>motor neuronshuman mesenchymal stem/stromal cellsfractalkine
spellingShingle Anastasia Sarikidi
Ekaterini Kefalakes
Christine S. Falk
Ruth Esser
Arnold Ganser
Nadine Thau-Habermann
Susanne Petri
Altered Immunomodulatory Responses in the CX3CL1/CX3CR1 Axis Mediated by hMSCs in an Early In Vitro SOD1<sup>G93A</sup> Model of ALS
Biomedicines
amyotrophic lateral sclerosis
SOD1<sup>G93A</sup>
motor neurons
human mesenchymal stem/stromal cells
fractalkine
title Altered Immunomodulatory Responses in the CX3CL1/CX3CR1 Axis Mediated by hMSCs in an Early In Vitro SOD1<sup>G93A</sup> Model of ALS
title_full Altered Immunomodulatory Responses in the CX3CL1/CX3CR1 Axis Mediated by hMSCs in an Early In Vitro SOD1<sup>G93A</sup> Model of ALS
title_fullStr Altered Immunomodulatory Responses in the CX3CL1/CX3CR1 Axis Mediated by hMSCs in an Early In Vitro SOD1<sup>G93A</sup> Model of ALS
title_full_unstemmed Altered Immunomodulatory Responses in the CX3CL1/CX3CR1 Axis Mediated by hMSCs in an Early In Vitro SOD1<sup>G93A</sup> Model of ALS
title_short Altered Immunomodulatory Responses in the CX3CL1/CX3CR1 Axis Mediated by hMSCs in an Early In Vitro SOD1<sup>G93A</sup> Model of ALS
title_sort altered immunomodulatory responses in the cx3cl1 cx3cr1 axis mediated by hmscs in an early in vitro sod1 sup g93a sup model of als
topic amyotrophic lateral sclerosis
SOD1<sup>G93A</sup>
motor neurons
human mesenchymal stem/stromal cells
fractalkine
url https://www.mdpi.com/2227-9059/10/11/2916
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