New iPSC –based model systems identify astrocyte subtypes vulnerability in neural disease

A new study by PhD students Prisca Leferink, Stephanie Dooves and Anne Hillen identified disease-specific pathways in astrocytic subtypes derived from patient stem cells. This study is published in Annals of Neurology.

Astrocytes have long been viewed as supportive cells of the brain, but over the last decade it has become clear that they play an important role in most, if not all, brain diseases. The authors developed a method to generate astrocytic subtypes from human and mouse induced pluripotent stem cells (iPSC). They used these iPSCs to show that a certain astrocytic subtype is more affected in the rare and severe genetic disorder Vanishing White Matter (VWM), for example presenting expression changes in genes involved in the immune system and extracellular matrix. Comparative studies between human and mouse cultures revealed human-specific disease mechanisms, such as neuronal and mitochondrial functioning. This study underscores the importance of considering astrocyte subtype vulnerability in neurological disease, influencing in vitro disease modeling outcomes, and targeting the correct cellular subtypes in therapeutic approaches.

 

From: Leferink et al. 2019: Fig. 1. Experimental overview. Fibroblasts from human and mouse, both VWM genotype and control / wt,  were reprogrammed to iPSCs, and differentiated to glial cells for various assays (1). The iPSCs were further differentiated to mouse and human grey and white matter astrocyte subtypes (2).  The different astrocyte subtypes were used as an in vitro model for VWM, in which oligodendrocyte maturation and apoptosis, morphology, proliferation rate, and mRNA expression was studied. From: Leferink et al. 2019: Fig. 1. Experimental overview. Fibroblasts from human and mouse, both VWM genotype and control / wt, were reprogrammed to iPSCs, and differentiated to glial cells for various assays (1). The iPSCs were further differentiated to mouse and human grey and white matter astrocyte subtypes (2). The different astrocyte subtypes were used as an in vitro model for VWM, in which oligodendrocyte maturation and apoptosis, morphology, proliferation rate, and mRNA expression was studied.
From: Leferink et al. 2019: Fig. 5. Human White and Grey Matter astrocyte subtypes differ in morphology and transcriptome. Immunostaining showed expression of astrocyte markers CD44 and SOX9 in control human iPSC-derived white matter (A) and grey matter astrocytes (B). Scale bar = 100 µm From: Leferink et al. 2019: Fig. 5. Human White and Grey Matter astrocyte subtypes differ in morphology and transcriptome. Immunostaining showed expression of astrocyte markers CD44 and SOX9 in control human iPSC-derived white matter (A) and grey matter astrocytes (B). Scale bar = 100 µm

The study is published in *Annals of Neurology*: https://doi.org/10.1002/ana.25585.

Leferink PS*, Dooves S*, Hillen AEJ*, Watanabe K, Jacobs G, Gasparotto L, Cornelissen-Steijger P, van der Knaap MS, Heine VM. Astrocyte subtype vulnerability in stem cell models of Vanishing White Matter. Ann Neurol. 2019 Aug 21. doi: 10.1002/ana.25585. *These authors contributed equally

A full-text pdf of the paper is available here.