Viral mediated knockdown of GATA6 in SMA iPSC‐derived astrocytes prevents motor neuron loss and microglial activation

• Published in: Glia 2022-05, Vol.70 (5), p.989-1004
• Main Authors: Allison, Reilly L., Welby, Emily, Khayrullina, Guzal, Burnett, Barrington G., Ebert, Allison D.
• Format: Article
• Language: English
• Subjects: Animals; Astrocytes; Astrocytes - metabolism; Atrophy; Child; Disease Models, Animal; GATA6 Transcription Factor - genetics; GATA6 Transcription Factor - metabolism; GATA6 Transcription Factor - pharmacology; Genetic disorders; Glial cells; Humans; Induced Pluripotent Stem Cells - metabolism; Inflammation; lentivirus; Microglia - metabolism; Motor neurons; Motor Neurons - pathology; Muscles; Muscular Atrophy, Spinal - genetics; Muscular Atrophy, Spinal - metabolism; Muscular Atrophy, Spinal - pathology; Nerve Degeneration - pathology; neurodegenerative disease; Neuromuscular diseases; Neurotoxicity; NF-κB protein; Pathology; Pediatrics; Phagocytosis; Pluripotency; pro‐inflammatory cytokines; SMN protein; Spinal cord; Spinal muscular atrophy; Stem cells; Survival of Motor Neuron 1 Protein - genetics; Survival of Motor Neuron 1 Protein - metabolism; Survival of Motor Neuron 1 Protein - therapeutic use
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.24153

Spinal muscular atrophy (SMA), a pediatric genetic disorder, is characterized by the profound loss of spinal cord motor neurons and subsequent muscle atrophy and death. Although the mechanisms underlying motor neuron loss are not entirely clear, data from our work and others support the idea that glial cells contribute to disease pathology. GATA6, a transcription factor that we have previously shown to be upregulated in SMA astrocytes, is negatively regulated by SMN (survival motor neuron) and can increase the expression of inflammatory regulator NFκB. In this study, we identified upregulated GATA6 as a contributor to increased activation, pro‐inflammatory ligand production, and neurotoxicity in spinal‐cord patterned astrocytes differentiated from SMA patient induced pluripotent stem cells. Reducing GATA6 expression in SMA astrocytes via lentiviral infection ameliorated these effects to healthy control levels. Additionally, we found that SMA astrocytes contribute to SMA microglial phagocytosis, which was again decreased by lentiviral‐mediated knockdown of GATA6. Together these data identify a role of GATA6 in SMA astrocyte pathology and further highlight glia as important targets of therapeutic intervention in SMA. Main Points GATA6 is upregulated in SMA astrocytes and is associated with increased glial activation, enhanced pro‐inflammatory ligand production, altered microglial morphology and phagocytosis, and motor neuron toxicity.