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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Detalles Bibliográficos
Autores: Mazuelas, Helena, Magallón-Lorenz, Míriam, Fernández-Rodríguez, Juana, Uriarte-Arrazola, Itziar, Richaud Patin, Yvonne, Terribas, Ernest, Villanueva, Alberto, Castellanos, Elisabeth, Blanco, Ignacio, Raya Chamorro, Ángel, Chojnacki, Jakub, Heyn, Holger, Romagosa, Cleofé, Lázaro García, Conxi, Gel, Bernat, Carrió, Meritxell, Serra, Eduard
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/52786
Acceso en línea:http://hdl.handle.net/10230/52786
http://dx.doi.org/10.1016/j.celrep.2022.110385
Access Level:acceso abierto
Palabra clave:RNA-seq
Schwann cell
Engraftment
Fibroblast
iPSC
Neural crest
Neurofibromatosis type 1
Plexiformneurofibroma
scRNA-seq
Spheroids
Descripción
Sumario: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 roadmap 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 RNA-seq data uncovers the presence of SC subpopulations at distinct differentiation states.

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