Biofabrication of a three dimensional human‐based personalized neurofibroma model

Abstract

Neurofibromas are the most characteristic feature of neurofibromatosis type 1 (NF1), a multisystemic disorder caused by aberrations in the neurofibromin gene (NF1). Despite significant progress over the last several years in understanding this disease, a suitable in vitro model to better mimic neurofibroma formation and growth has yet to be described. There is therefore a need to establish an in vitro, three dimensional model that allows the incorporation of multicellular lineages and the modulation of the cellular microenvironment—known to be important for cellular crosstalk and distribution of soluble factors—to study neurofibroma biology and morphogenesis. A self‐assembly approach was used to generate tissue‐engineered skins (TES) in which patient‐derived spheroids made of NF1‐associated Schwann cells and fibroblasts were seeded. We describe the first in vitro three dimensional neurofibroma model—directly derived from NF1 patients presenting with histopathological features—having an ECM protein expression profile quite similar to that of a native tumor. We observed efficient incorporation, proliferation, and migration of spheroids within NF1‐TES over time. This biotechnological approach could provide a unique tool for precision medicine targeting NF1 and for assessing the tumorigenic properties of each NF1 gene mutation linked to tumor formation.