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Science beyond Barriers

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Neurobiology

2022
Cell Reports

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

Authors:

Mazuelas, H., Magallón-Lorenz, M., Fernández-Rodríguez, J., Uriarte-Arrazola, I., Richaud-Patin, Y., Terribas, E., ... & Serra, E.

Keywords:

neurofibromatosis type 1, plexiformneurofibroma, Schwann cell, neural crest, iPSC, RNA-seq, scRNA-seq, engraftment, spheroids, fibroblast

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.

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