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

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

doi:http://dx.doi.org/10.1016/j.celrep.2022.110385

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

Citation

Mazuelas H, Magallón-Lorenz M, Fernández-Rodríguez J, Uriarte-Arrazola I, Richaud-Patin Y, Terribas E, Villanueva A, Castellanos E, Blanco I, Raya Á, Chojnacki J, Heyn H, Romagosa C, Lázaro C, Gel B, Carrió M, Serra E. Modeling iPSC-derived human neurofibroma-like tumors in mice uncovers the heterogeneity of Schwann cells within plexiform neurofibromas. Cell Rep. 2022 Feb 15;38(7):110385. DOI: 10.1016/j.celrep.2022.110385

Abstract

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.