Modeling iPSC-derived human neurofibroma-like tumors in mice uncovers the heterogeneity of Schwann cells within plexiform neurofibromas

Plexiform 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 ce...

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Detalhes bibliográficos
Autores: Mazuelas, Helena, Magallón Lorenz, Miriam, Fernández Rodríguez, Juana, Uriarte Arrazola, Itziar, Richaud-Patin, Yvonne, Terribas, Ernest, Villanueva Garatachea, Alberto, Castellanos, Elisabeth, Blanco Guillermo, Ignacio, Raya Chamorro, Ángel, Chojnacki, Jakub, Heyn, Holger, Romagosa Pérez-Portabella, Cleofé, Lázaro García, Conxi, Gel Moreno, Bernat, Carrió, Meritxell, Serra Arenas, Eduard
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/184276
Acesso em linha:https://hdl.handle.net/2445/184276
Access Level:acceso abierto
Palavra-chave:Neurofibromatosi
Genètica
Neurofibromatosis
Genetics
Descrição
Resumo:Plexiform 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.

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