Mazuelas, HelenaMagallón Lorenz, MiriamFernández Rodríguez, JuanaUriarte Arrazola, ItziarRichaud-Patin, YvonneTerribas, ErnestVillanueva Garatachea, AlbertoCastellanos, ElisabethBlanco Guillermo, IgnacioRaya Chamorro, ÁngelChojnacki, JakubHeyn, HolgerRomagosa Pérez-Portabella, CleoféLázaro García, ConxiGel Moreno, BernatCarrió, MeritxellSerra Arenas, Eduard2022-03-222022-03-222022-02-012211-1247https://hdl.handle.net/2445/184276Plexiform neurofibromas (pNFs) are developmental tumors that appear in neurofibromatosis type 1 individuals, constituting a major source of morbidity and potentially transforming into a highly metastatic sarcoma (MPNST). pNFs arise after NF1 inactivation in a cell of the neural crest (NC)-Schwann cell (SC) lineage. Here, we develop an iPSC-based NC-SC in vitro differentiation system and construct a lineage expression road map for the analysis of different 2D and 3D NF models. The best model consists of generating heterotypic spheroids (neurofibromaspheres) composed of iPSC-derived differentiating NF1((-/-)) SCs and NF1((+/-)) pNF-derived fibroblasts (Fbs). Neurofibromaspheres form by maintaining highly proliferative NF1((-/-)) cells committed to the NC-SC axis due to SC-SC and SC-Fb interactions, resulting in SC linage cells at different maturation points. Upon engraftment on the mouse sciatic nerve, neurofibromaspheres consistently generate human NF-like tumors. Analysis of expression roadmap genes in human pNF single-cell RNAseq data uncovers the presence of SC subpopulations at distinct differentiation states.25 p.application/pdfengcc by-nc-nd (c) Mazuelas, Helena et al, 2022http://creativecommons.org/licenses/by-nc-nd/3.0/es/NeurofibromatosiGenèticaNeurofibromatosisGeneticsinfo:eu-repo/semantics/article2022-03-22info:eu-repo/semantics/openAccess35172160