A human model of histiocyte associated neurodegeneration

Langerhans cell histiocytosis (LCH) is a highly heterogenous inflammatory mononuclear cell disorder caused by activating somatic mosaic mutations in the mitogen-activated protein kinase (MAPK) pathway, most commonly BRAFV600E. An unpredictable subset of LCH patients develop a heterogenous progressive and incurable neurodegenerative disease (LCH-ND).

Here we generate a human induced pluripotent stem cell model from patients with somatic hematologic mosaicism for BRAFV600E. Brain macrophage/microglia from LCH iPSCs exhibit disease specific pathogenic features of MAPK activation. Stepwise differentiation identified hematopoietic progenitors as hyperproliferative, whereas brain macrophages were apoptosis resistant.