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

Abstract

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.
Original languageEnglish
JournalAnnals of Neurology
Volume86
DOIs
Publication statusPublished - 1 Nov 2019

Cite this

@article{b310b7f6531341c1be980eedda39b97b,
title = "Astrocyte Subtype Vulnerability in Stem Cell Models of Vanishing White Matter",
abstract = "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.",
author = "Leferink, {Prisca S.} and Stephanie Dooves and Hillen, {Anne E. J.} and Kyoko Watanabe and Gerbren Jacobs and Lisa Gasparotto and Paulien Cornelissen-Steijger and {van der Knaap}, {Marjo S.} and Heine, {Vivi M.}",
year = "2019",
month = "11",
day = "1",
doi = "10.1002/ana.25585",
language = "English",
volume = "86",
journal = "Annals of Neurology",
issn = "0364-5134",
publisher = "John Wiley and Sons Inc.",

}

Astrocyte Subtype Vulnerability in Stem Cell Models of Vanishing White Matter. / Leferink, Prisca S.; Dooves, Stephanie; Hillen, Anne E. J.; Watanabe, Kyoko; Jacobs, Gerbren; Gasparotto, Lisa; Cornelissen-Steijger, Paulien; van der Knaap, Marjo S.; Heine, Vivi M.

In: Annals of Neurology, Vol. 86, 01.11.2019.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Astrocyte Subtype Vulnerability in Stem Cell Models of Vanishing White Matter

AU - Leferink, Prisca S.

AU - Dooves, Stephanie

AU - Hillen, Anne E. J.

AU - Watanabe, Kyoko

AU - Jacobs, Gerbren

AU - Gasparotto, Lisa

AU - Cornelissen-Steijger, Paulien

AU - van der Knaap, Marjo S.

AU - Heine, Vivi M.

PY - 2019/11/1

Y1 - 2019/11/1

N2 - 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.

AB - 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.

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U2 - 10.1002/ana.25585

DO - 10.1002/ana.25585

M3 - Article

VL - 86

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

ER -