TY - JOUR
T1 - Therapeutic potential of human stem cell transplantations for Vanishing White Matter
T2 - A quest for the Goldilocks graft
AU - Hillen, Anne E.J.
AU - Leferink, Prisca S.
AU - Breeuwsma, Nicole B.
AU - Dooves, Stephanie
AU - Bergaglio, Talia
AU - Van der Knaap, Marjo S.
AU - Heine, Vivi M.
N1 - 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.
PY - 2022/9
Y1 - 2022/9
N2 - 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.
AB - 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.
KW - Vanishing white matter
KW - cell transplantation
KW - glia
KW - human pluripotent stem cells
KW - leukodystrophy
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U2 - https://doi.org/10.1111/cns.13872
DO - https://doi.org/10.1111/cns.13872
M3 - Article
C2 - 35778846
SN - 1755-5930
VL - 28
SP - 1315
EP - 1325
JO - CNS Neuroscience and Therapeutics
JF - CNS Neuroscience and Therapeutics
IS - 9
ER -