Medical College of Wisconsin
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ALS iPSC-derived microglia and motor neurons respond to astrocyte-targeted IL-10 and CCL2 modulation. Hum Mol Genet 2024 Feb 28;33(6):530-542

Date

12/22/2023

Pubmed ID

38129120

DOI

10.1093/hmg/ddad209

Scopus ID

2-s2.0-85186709230 (requires institutional sign-in at Scopus site)   2 Citations

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons (MNs). The loss of MNs in ALS leads to muscle weakness and wasting, respiratory failure, and death often within two years of diagnosis. Glial cells in ALS show aberrant expression of pro-inflammatory and neurotoxic proteins associated with activation and have been proposed as ideal therapeutic targets. In this study, we examined astrocyte-targeted treatments to reduce glial activation and neuron pathology using cells differentiated from ALS patient-derived iPSC carrying SOD1 and C9ORF72 mutations. Specifically, we tested the ability of increasing interleukin 10 (IL-10) and reducing C-C motif chemokine ligand 2 (CCL2/MCP-1) signaling targeted to astrocytes to reduce activation phenotypes in both astrocytes and microglia. Overall, we found IL10/CCL2NAb treated astrocytes to support anti-inflammatory phenotypes and reduce neurotoxicity, through different mechanisms in SOD1 and C9ORF72 cultures. We also found altered responses of microglia and motor neurons to astrocytic influences when cells were cultured together rather than in isolation. Together these data support IL-10 and CCL2 as non-mutation-specific therapeutic targets for ALS and highlight the role of glial-mediated pathology in this disease.

Author List

Allison RL, Ebert AD

Author

Allison D. Ebert PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Amyotrophic Lateral Sclerosis
Astrocytes
C9orf72 Protein
Chemokine CCL2
Humans
Induced Pluripotent Stem Cells
Interleukin-10
Microglia
Motor Neurons
Neurodegenerative Diseases
Superoxide Dismutase-1