A human model of histiocyte associated neurodegeneration

Neurodegenerative diseases are increasingly recognized as having an innate immune component to both disease onset and progression, but the extent and mechanisms are incompletely understood. 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. Through application of cerebral organoids and a humanized murine xenotransplantation model we identify marked heterogeneity of differentiation potential within clonal BRAFV600E lines in vivo. This model phenocopied human specific phenotypes not found in murine models including dense basal ganglia foci of abnormal macrophages and caused marked neurodegeneration and astrogliosis due to BRAFV600E microglia. This approach will allow for human specific in vitro and preclinical testing of therapeutics in LCH-ND