Microglia, the only lifelong resident immune cells of the central nervous system (CNS), are highly specialized macrophages which have been recognized to play a crucial role in neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Adrenoleukodystrophy (ALD). However, in contrast to other cell types of the human CNS, bona fide microglia have not yet been derived from cultured human pluripotent stem cells. Here we establish a robust and efficient protocol for the rapid production of microglia-like cells from human embryonic stem (ES) and induced pluripotent stem (iPS) cells that uses defined serum-free culture conditions. These in vitro pluripotent stem cell-derived microglia-like cells (termed pMGLs) faithfully recapitulate the expected ontogeny and characteristics of their in vivo counterparts and resemble primary fetal human and mouse microglia. We generated these cells from multiple disease-specific cell lines, and find that pMGLs derived from MeCP2 mutant hES cells are smaller than their isogenic controls. We further describe a culture platform to study integration and live behavior of pMGLs in organotypic 3D-cultures. This modular differentiation system allows the study of microglia in highly defined conditions, as they mature in response to developmentally relevant cues, and provides a framework to study the long-term interactions of microglia residing in a tissue-like environment.
Objective An approved definition of the term leukodystrophy does not currently exist. The lack of a precise case definition hampers efforts to study the epidemiology and the relevance of genetic white matter disorders to public health. Method Thirteen experts at multiple institutions participated in iterative consensus building surveys to achieve definition and classification of disorders as leukodystrophies using a modified Delphi approach. Results A case definition for the leukodystrophies was achieved, and a total of 30 disorders were classified under this definition. In addition, a separate set of disorders with heritable white matter abnormalities but not meeting criteria for leukodystrophy, due to presumed primary neuronal involvement and prominent systemic manifestations, was classified as genetic leukoencephalopathies (gLE). Interpretation A case definition of leukodystrophies and classification of heritable white matter disorders will permit more detailed epidemiologic studies of these disorders.
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