Reprogramming Captures the Genetic and Tumorigenic Properties of Neurofibromatosis Type 1 Plexiform Neurofibromas

• Published in: Stem cell reports Vol. 12; no. 2; pp. 411 - 426
• Main Authors: Carrió, Meritxell, Mazuelas, Helena, Richaud-Patin, Yvonne, Gel, Bernat, Terribas, Ernest, Rosas, Imma, Jimenez-Delgado, Senda, Biayna, Josep, Vendredy, Leen, Blanco, Ignacio, Castellanos, Elisabeth, Lázaro, Conxi, Raya, Ángel, Serra, Eduard
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.02.2019; Elsevier
• Subjects: Adolescent; Adult; Aged; benign tumor; Biomarkers - blood; Carcinogenesis - genetics; Cell Proliferation - genetics; Cellular Reprogramming - genetics; Child; Female; Genes, Tumor Suppressor - physiology; Genetic Predisposition to Disease - genetics; Genotype; Humans; iPSC; Male; Middle Aged; Mutation - genetics; Neural Crest - physiology; neural crest stem cell; Neurofibroma, Plexiform - blood; Neurofibroma, Plexiform - genetics; Neurofibromatosis 1 - blood; Neurofibromatosis 1 - genetics; neurofibromatosis type 1; NF1; plexiform neurofibroma; Resource; Schwann cell; Schwann Cells - physiology; Young Adult; benign tumor; Schwann cell; neural crest stem cell; iPSC; neurofibromatosis type 1; NF1; plexiform neurofibroma
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2019.01.001

Neurofibromatosis type 1 (NF1) is a tumor predisposition genetic disease caused by mutations in the NF1 tumor suppressor gene. Plexiform neurofibromas (PNFs) are benign Schwann cell (SC) tumors of the peripheral nerve sheath that develop through NF1 inactivation and can progress toward a malignant soft tissue sarcoma. There is a lack of non-perishable model systems to investigate PNF development. We reprogrammed PNF-derived NF1(−/−) cells, descendants from the tumor originating cell. These NF1(−/−)-induced pluripotent stem cells (iPSCs) captured the genomic status of PNFs and were able to differentiate toward neural crest stem cells and further to SCs. iPSC-derived NF1(−/−) SCs exhibited a continuous high proliferation rate, poor myelination ability, and a tendency to form 3D spheres that expressed the same markers as their PNF-derived primary SC counterparts. They represent a valuable model to study and treat PNFs. PNF-derived iPSC lines were banked for making them available. [Display omitted] •We generated iPSCs from neurofibromatosis type 1 plexiform neurofibroma (PNF) cells•PNF-derived iPSCs were differentiated into neural crest and Schwann cells (SCs)•iPSC-differentiated NF1(−/−) SCs exhibit a high proliferation rate and form spheres•Sphere-forming SCs express the same markers as their primary PNF counterparts In this article, Eduard Serra and colleagues describe the generation of iPSCs directly from plexiform neurofibromas (PNFs), benign Schwann cell (SC) tumors associated with neurofibromatosis type 1. iPSCs bearing the double inactivation of the NF1 gene were differentiated into SCs that exhibited a high proliferation rate, a poor myelination ability, and a tendency to form spheres, resembling PNF-derived SCs.