iPSC-derived reactive astrocytes from patients with multiple-sclerosis protect cocultured neurons in inflammatory conditions

Janis Kerkering; Bakhrom Muinjonov; Kamil Sebastian Rosiewicz; Sebastian Diecke; Charlotte Biese; Juliane Schiweck; Claudia Chien; Dario Zocholl; Thomas Conrad; Friedemann Paul; Marlen Alisch; Volker Siffrin

doi:10.1172/JCI164637

¹Experimental and Clinical Research Center (ECRC), Charité - Universitätsmedizin Berlin and Max Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

²Technology Platform Pluripotent Stem Cells, Max Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

³Institute of Biochemistry, Charité - Universitätsmedizin Berlin, Berlin, Germany

⁴Institute of Biometry and Clinical Epidemiology, Charité - Universitätsmedizin Berlin, Berlin, Germany

⁵Genomics Technology Platform, Charité - UniversitäMax Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

Find articles by Kerkering, J. in: JCI | PubMed | Google Scholar

¹Experimental and Clinical Research Center (ECRC), Charité - Universitätsmedizin Berlin and Max Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

²Technology Platform Pluripotent Stem Cells, Max Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

³Institute of Biochemistry, Charité - Universitätsmedizin Berlin, Berlin, Germany

⁴Institute of Biometry and Clinical Epidemiology, Charité - Universitätsmedizin Berlin, Berlin, Germany

⁵Genomics Technology Platform, Charité - UniversitäMax Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

Find articles by Muinjonov, B. in: JCI | PubMed | Google Scholar |

¹Experimental and Clinical Research Center (ECRC), Charité - Universitätsmedizin Berlin and Max Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

²Technology Platform Pluripotent Stem Cells, Max Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

³Institute of Biochemistry, Charité - Universitätsmedizin Berlin, Berlin, Germany

⁴Institute of Biometry and Clinical Epidemiology, Charité - Universitätsmedizin Berlin, Berlin, Germany

⁵Genomics Technology Platform, Charité - UniversitäMax Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

Find articles by Rosiewicz, K. in: JCI | PubMed | Google Scholar |

¹Experimental and Clinical Research Center (ECRC), Charité - Universitätsmedizin Berlin and Max Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

²Technology Platform Pluripotent Stem Cells, Max Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

³Institute of Biochemistry, Charité - Universitätsmedizin Berlin, Berlin, Germany

⁴Institute of Biometry and Clinical Epidemiology, Charité - Universitätsmedizin Berlin, Berlin, Germany

⁵Genomics Technology Platform, Charité - UniversitäMax Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

Find articles by Diecke, S. in: JCI | PubMed | Google Scholar

¹Experimental and Clinical Research Center (ECRC), Charité - Universitätsmedizin Berlin and Max Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

²Technology Platform Pluripotent Stem Cells, Max Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

³Institute of Biochemistry, Charité - Universitätsmedizin Berlin, Berlin, Germany

⁴Institute of Biometry and Clinical Epidemiology, Charité - Universitätsmedizin Berlin, Berlin, Germany

⁵Genomics Technology Platform, Charité - UniversitäMax Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

Find articles by Biese, C. in: JCI | PubMed | Google Scholar

¹Experimental and Clinical Research Center (ECRC), Charité - Universitätsmedizin Berlin and Max Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

²Technology Platform Pluripotent Stem Cells, Max Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

³Institute of Biochemistry, Charité - Universitätsmedizin Berlin, Berlin, Germany

⁴Institute of Biometry and Clinical Epidemiology, Charité - Universitätsmedizin Berlin, Berlin, Germany

⁵Genomics Technology Platform, Charité - UniversitäMax Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

Find articles by Schiweck, J. in: JCI | PubMed | Google Scholar |

¹Experimental and Clinical Research Center (ECRC), Charité - Universitätsmedizin Berlin and Max Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

²Technology Platform Pluripotent Stem Cells, Max Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

³Institute of Biochemistry, Charité - Universitätsmedizin Berlin, Berlin, Germany

⁴Institute of Biometry and Clinical Epidemiology, Charité - Universitätsmedizin Berlin, Berlin, Germany

⁵Genomics Technology Platform, Charité - UniversitäMax Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

Find articles by Chien, C. in: JCI | PubMed | Google Scholar |

¹Experimental and Clinical Research Center (ECRC), Charité - Universitätsmedizin Berlin and Max Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

²Technology Platform Pluripotent Stem Cells, Max Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

³Institute of Biochemistry, Charité - Universitätsmedizin Berlin, Berlin, Germany

⁴Institute of Biometry and Clinical Epidemiology, Charité - Universitätsmedizin Berlin, Berlin, Germany

⁵Genomics Technology Platform, Charité - UniversitäMax Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

Find articles by Zocholl, D. in: JCI | PubMed | Google Scholar |

¹Experimental and Clinical Research Center (ECRC), Charité - Universitätsmedizin Berlin and Max Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

²Technology Platform Pluripotent Stem Cells, Max Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

³Institute of Biochemistry, Charité - Universitätsmedizin Berlin, Berlin, Germany

⁴Institute of Biometry and Clinical Epidemiology, Charité - Universitätsmedizin Berlin, Berlin, Germany

⁵Genomics Technology Platform, Charité - UniversitäMax Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

Find articles by Conrad, T. in: JCI | PubMed | Google Scholar |

¹Experimental and Clinical Research Center (ECRC), Charité - Universitätsmedizin Berlin and Max Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

²Technology Platform Pluripotent Stem Cells, Max Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

³Institute of Biochemistry, Charité - Universitätsmedizin Berlin, Berlin, Germany

⁴Institute of Biometry and Clinical Epidemiology, Charité - Universitätsmedizin Berlin, Berlin, Germany

⁵Genomics Technology Platform, Charité - UniversitäMax Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

Find articles by Paul, F. in: JCI | PubMed | Google Scholar

¹Experimental and Clinical Research Center (ECRC), Charité - Universitätsmedizin Berlin and Max Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

²Technology Platform Pluripotent Stem Cells, Max Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

³Institute of Biochemistry, Charité - Universitätsmedizin Berlin, Berlin, Germany

⁴Institute of Biometry and Clinical Epidemiology, Charité - Universitätsmedizin Berlin, Berlin, Germany

⁵Genomics Technology Platform, Charité - UniversitäMax Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

Find articles by Alisch, M. in: JCI | PubMed | Google Scholar

¹Experimental and Clinical Research Center (ECRC), Charité - Universitätsmedizin Berlin and Max Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

²Technology Platform Pluripotent Stem Cells, Max Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

³Institute of Biochemistry, Charité - Universitätsmedizin Berlin, Berlin, Germany

⁴Institute of Biometry and Clinical Epidemiology, Charité - Universitätsmedizin Berlin, Berlin, Germany

⁵Genomics Technology Platform, Charité - UniversitäMax Delbrück Center of Molecular Medicine in the Helmholtz Association, Berlin, Germany

Find articles by Siffrin, V. in: JCI | PubMed | Google Scholar |

J Clin Invest. https://doi.org/10.1172/JCI164637.
Copyright © 2023, Kerkering et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published May 23, 2023 - Version history

Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system (CNS). The individual course is highly variable with complete remission in some patients and relentless courses in others. We generated induced pluripotent stem cells (iPSCs) to investigate possible mechanisms in benign MS (BMS), compared to progressive MS (PMS). We differentiated neurons and astrocytes that were then stressed with inflammatory cytokines typically associated with MS. TNFα/IL-17A treatment increased neurite damage in MS neurons irrespective of clinical phenotypes. In contrast, TNFα/IL-17A-reactive BMS astrocytes cultured with healthy control (HC) neurons exhibited significantly decreased axonal damage, compared to PMS astrocytes. Accordingly, single cell transcriptomic analysis of BMS-astrocyte co-cultured neurons demonstrated upregulated pathways of neuronal resilience, namely these astrocytes revealed differential growth factor expression. Moreover, supernatants from BMS astrocyte-neuron co-cultures rescued TNFα/IL-17-induced neurite damage. This process was associated with the unique expression of the growth factors, LIF and TGF-β1, as induced by TNFα/IL-17 and JAK-STAT activation. Our findings highlight a potential therapeutic role of modulating astrocyte phenotypes that generate a neuroprotective milieu preventing permanent neuronal damage.

Version 1 (May 23, 2023): In-Press Preview

iPSC-derived reactive astrocytes from patients with multiple-sclerosis protect cocultured neurons in inflammatory conditions

Janis Kerkering,¹ Bakhrom Muinjonov,¹ Kamil Sebastian Rosiewicz,¹ Sebastian Diecke,² Charlotte Biese,¹ Juliane Schiweck,³ Claudia Chien,¹ Dario Zocholl,⁴ Thomas Conrad,⁵ Friedemann Paul,¹ Marlen Alisch,¹ and Volker Siffrin¹

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iPSC-derived reactive astrocytes from patients with multiple-sclerosis protect cocultured neurons in inflammatory conditions

Janis Kerkering,1 Bakhrom Muinjonov,1 Kamil Sebastian Rosiewicz,1 Sebastian Diecke,2 Charlotte Biese,1 Juliane Schiweck,3 Claudia Chien,1 Dario Zocholl,4 Thomas Conrad,5 Friedemann Paul,1 Marlen Alisch,1 and Volker Siffrin1

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Janis Kerkering,¹ Bakhrom Muinjonov,¹ Kamil Sebastian Rosiewicz,¹ Sebastian Diecke,² Charlotte Biese,¹ Juliane Schiweck,³ Claudia Chien,¹ Dario Zocholl,⁴ Thomas Conrad,⁵ Friedemann Paul,¹ Marlen Alisch,¹ and Volker Siffrin¹