Abstract：
BACKGROUND: 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.
OBJECTIVE: 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.
OBJECTIVE: 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.
摘要：
背景：白质消失（VWM）是一种导致神经功能障碍和早期死亡的脑白质营养不良。星形胶质细胞被指示为治疗靶标，因为它们在VWM病理学中的核心作用。先前使用原代小鼠神经胶质前体的细胞替代疗法在表型上改善了VWM小鼠。
目的：本研究的目的是确定人干细胞衍生的神经胶质细胞替代疗法对VWM的转化潜力。我们从人类多能干细胞中产生了各种神经胶质细胞类型，以鉴定成功改善VWM小鼠模型疾病标志的人类细胞群。评估了细胞移植物对运动技能和VWM脑病理学的影响。
结果：人类神经胶质前体群体的移植改善了VWM表型。移植后的细胞命运部分反映了这些细胞的内在特性，但也受到宿主微环境的影响。引人注目的是，与健康大脑相比，移植到VWM大脑中的细胞在白质和灰质中的扩散是不同的。
结论：人神经胶质细胞群的移植对VWM具有治疗作用。为了进一步翻译到诊所，VWM患者大脑中的微环境应被视为细胞替代疗法的重要调节剂。
目的：本研究的目的是确定人干细胞衍生的神经胶质细胞替代疗法对VWM的转化潜力。我们从人类多能干细胞中产生了各种神经胶质细胞类型，以鉴定成功改善VWM小鼠模型疾病标志的人类细胞群。评估了细胞移植物对运动技能和VWM脑病理学的影响。
结果：人类神经胶质前体群体的移植改善了VWM表型。移植后的细胞命运部分反映了这些细胞的内在特性，但也受到宿主微环境的影响。引人注目的是，与健康大脑相比，移植到VWM大脑中的细胞在白质和灰质中的扩散是不同的。
结论：人神经胶质细胞群的移植对VWM具有治疗作用。为了进一步翻译到诊所，VWM患者大脑中的微环境应被视为细胞替代疗法的重要调节剂。
