This study from the Le Lab reports two different model systems that give rise to plexiform neurofibroma and to nodular cutaneous neurofibroma. The first model uses induced human pluripotent stem cells (hiPSCs) harboring patient-based NF1 mutations to generate humanized neurofibroma and MPNST mouse models that phenocopy the analogous tumors in patients. SOX10/HOXb7-expressing NF1–/– hiPSC were first differentiated into Schwann cell precursors (SCPs) and then implanted into the sciatic nerve of host nude mice where they formed bona fide neurofibromas with high levels of SOX10 expression. Using hiPSC-differentiated SCPs and mouse E13.5 dorsal root ganglion/nerve root neurosphere cells DNCSs (which contain the cells of origin for plexiform neurofibroma), they also discovered that NF1 loss impairs differentiation of the Schwann cell lineage by arresting the cells in a more stem-like state, thus expanding the population of potential cells of origin for neurofibroma.
In another model, both Nf1 alleles were inactivated in mouse Sox10-positive cells. This resulted in the development of classic nodular cutaneous and plexiform neurofibroma that also completely recapitulated their human counterparts. This mouse model represents the first nodular cutaneous neurofibroma model to be reported.
Both of these models provide powerful, tractable platforms for future therapeutic discovery and preclinical testing.