Therapeutic potential of human stem cell transplantations for Vanishing White Matter: A quest for the Goldilocks graft

Anne E.J. Hillen, Prisca S. Leferink, Nicole B. Breeuwsma, Stephanie Dooves, Talia Bergaglio, Marjo S. Van der Knaap, Vivi M. Heine*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Introduction: Vanishing white matter (VWM) is a leukodystrophy that leads to neurological dysfunction and early death. Astrocytes are indicated as therapeutic target, because of their central role in VWM pathology. Previous cell replacement therapy using primary mouse glial precursors phenotypically improved VWM mice. Aims: The aim of this study was to determine the translational potential of human stem cell-derived glial cell replacement therapy for VWM. We generated various glial cell types from human pluripotent stem cells in order to identify a human cell population that successfully ameliorates disease hallmarks of a VWM mouse model. The effects of cell grafts on motor skills and VWM brain pathology were assessed. Results: Transplantation of human glial precursor populations improved the VWM phenotype. The intrinsic properties of these cells were partially reflected by cell fate post-transplantation, but were also affected by the host microenvironment. Strikingly, the spread of transplanted cells into the white matter versus the gray matter was different when grafted into the VWM brain as compared to a healthy brain. Conclusions: Transplantation of human glial cell populations can have therapeutic effects for VWM. For further translation to the clinic, the microenvironment in the VWM patient brain should be considered as an important moderator of cell replacement therapy.

Original languageEnglish
Pages (from-to)1315-1325
Number of pages11
JournalCNS Neuroscience and Therapeutics
Volume28
Issue number9
Early online date1 Jul 2022
DOIs
Publication statusPublished - Sept 2022

Bibliographical note

Funding Information:
This study was financially supported by the NWO Spinoza grant (M.S.v.d.K.), ZonMw VIDI research grant 91712343 (V.M.H.), the ZonMw TAS IDB project 116005006 (V.M.H.), the European Leukodystrophy Foundation (ELA; #2014–012 l1), and E‐Rare Joint Call project 9003037601 (V.M.H. and M.S.v.d.K.)

Funding Information:
We thank Marit de Vries for support with ISH analysis and Lisa Gasparotto for genotyping the animals.

Publisher Copyright:
© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.

Funding

This study was financially supported by the NWO Spinoza grant (M.S.v.d.K.), ZonMw VIDI research grant 91712343 (V.M.H.), the ZonMw TAS IDB project 116005006 (V.M.H.), the European Leukodystrophy Foundation (ELA; #2014–012 l1), and E‐Rare Joint Call project 9003037601 (V.M.H. and M.S.v.d.K.) We thank Marit de Vries for support with ISH analysis and Lisa Gasparotto for genotyping the animals.

FundersFunder number
European Leukodystrophy Foundation2014–012 l1, 9003037601
Marit de Vries
ZonMw TAS IDB116005006
ZonMw91712343
ZonMw
Nederlandse Organisatie voor Wetenschappelijk Onderzoek

    Keywords

    • cell transplantation
    • glia
    • human pluripotent stem cells
    • leukodystrophy
    • Vanishing white matter

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