Astrocyte Subtype Vulnerability in Stem Cell Models of Vanishing White Matter

Prisca S Leferink, Stephanie Dooves, Anne E J Hillen, Kyoko Watanabe, Gerbren Jacobs, Lisa Gasparotto, Paulien Cornelissen-Steijger, Marjo S van der Knaap, Vivi M Heine

Research output: Contribution to JournalArticleAcademicpeer-review


OBJECTIVE: Astrocytes have gained attention as important players in neurological disease. In line with their heterogeneous character, defects in specific astrocyte subtypes have been identified. Leukodystrophy vanishing white matter (VWM) shows selective vulnerability in white matter astrocytes, but the underlying mechanisms remain unclear. Induced pluripotent stem cell technology is being extensively explored in studies of pathophysiology and regenerative medicine. However, models for distinct astrocyte subtypes for VWM are lacking, thereby hampering identification of disease-specific pathways.

METHODS: Here, we characterize human and mouse pluripotent stem cell-derived gray and white matter astrocyte subtypes to generate an in vitro VWM model. We examined morphology and functionality, and used coculture methods, high-content microscopy, and RNA sequencing to study VWM cultures.

RESULTS: We found intrinsic vulnerability in specific astrocyte subpopulations in VWM. When comparing VWM and control cultures, white matter-like astrocytes inhibited oligodendrocyte maturation, and showed affected pathways in both human and mouse cultures, involving the immune system and extracellular matrix. Interestingly, human white matter-like astrocytes presented additional, human-specific disease mechanisms, such as neuronal and mitochondrial functioning.

INTERPRETATION: Astrocyte subtype cultures revealed disease-specific pathways in VWM. Cross-validation of human- and mouse-derived protocols identified human-specific disease aspects. This study provides new insights into VWM disease mechanisms, which helps the development of in vivo regenerative applications, and we further present strategies to study astrocyte subtype vulnerability in neurological disease. ANN NEUROL 2019;86:780-792.

Original languageEnglish
Pages (from-to)780-792
Number of pages13
JournalAnnals of Neurology
Issue number5
Publication statusPublished - Nov 2019

Bibliographical note

© 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.


This research is funded by a ZonMw VIDI research grant (91712343, V.M.H.), a European Leukodystrophy Association research grant (2014-012L1, V.M.H.), an E-Rare Joint Call project (9003037601, V.M.H.), and an NWO Spinoza grant (M.S.v.d.K.). We thank J. Broeke for his help with the calcium imaging of the astrocytes and A. Badia for her help with the morphological analysis using Columbus software.

FundersFunder number
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Association Européenne contre les Leucodystrophies2014-012L1, 9003037601


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