A new cell model to advance research into NF2-related schwannomatosis

A study led by the Clinical Genomics Unit (UGC) at IGTP, within the framework of the Spanish State Reference Centre (CSUR) for Phacomatoses, has established a new cell model to advance research into NF2-related schwannomatosis (SWN-NF2), a rare genetic disease. The work, published in the journal Genes & Disease, describes the generation and characterisation of cell spheroids derived from induced pluripotent stem cells (iPSC)-a type of stem cell capable of transforming into almost any cell type-that reproduce the alterations observed in tumours associated with the disease.

SWN-NF2 is an autosomal dominant syndrome caused by mutations in the NF2 gene, affecting approximately 1 in every 28,000 births worldwide. It is characterised by the presence of vestibular schwannomas, often combined with other schwannomas, meningiomas and ependymomas. It is classified as autosomal dominant because the mutation occurs in a non-sex-linked gene, and a single altered copy- inherited from either parent-is sufficient for the condition to manifest.

Until now, research into this disease has been hampered by the lack of reliable human cell models that accurately mimic the cells involved in tumour development.

In this study, the research team created several cell models derived from human stem cells. Six different lines were generated: three with a single NF2 gene mutation, mimicking the typical genetic profile of affected individuals, and three with alterations in both copies of the gene, as observed in tumour cells. These lines were developed using patient samples and advanced gene-editing techniques (CRISPR/Cas9).

For the first time, these stem cells were differentiated into Schwann cells-the cell type involved in the disease-using a three-dimensional system that produces cellular structures (spheroids) carrying the same mutations found in patients' tumours.

These structures were thoroughly analysed and shown to share both genetic and functional features with real tumour cells. The findings confirmed that they faithfully reproduce the molecular changes found in tumours from NF2 patients, including the abnormal activation of previously described cellular mechanisms.

"This model provides an innovative and faithful tool to study the role of the NF2 gene under controlled conditions and to evaluate new therapeutic strategies," says Dr Elisabeth Castellanos. "Moreover, the pluripotency of these cells opens the door to studying other cell types and tumours associated with the disease."

This cell system therefore offers a stable and reproducible platform to further understand the pathogenesis of the disease and to develop preclinical assays in a physiologically relevant context. As iPSCs can differentiate into various cell types, the model may also be useful for investigating other NF2-related tumours beyond schwannomas.

The generated cell lines will be made available to the scientific community to promote collaborative research in this field. The project has been supported by several patient associations, including AcNefi, Chromo22, Fundación Proyecto Neurofibromatosis ' FPNF, and the Asociación de Afectados por la Neurofibromatosis, both through sample donation and partial funding of the study.

Reference

Núria Catasús, Gemma Casals-Sendra, Miguel Torres-Martin, Inma Rosas, Bernd Kuebler, Helena Mazuelas, Emilio Amilibia, Begoña Aran, Anna Veiga, Ángel Raya, Bernat Gel, Ignacio Blanco, Eduard Serra, Meritxell Carrió, Elisabeth Castellanos. iPSC-based merlin-deficient Schwann cell-like spheroids as an in vitro system for studying NF2 pathogenesis. Genes & Diseases. 2025, DOI: https://doi.org/10.1016/j.gendis.2025.101615.