Cellular origin, tumour progression and pathogenic mechanisms of cutaneous neurofibromas revealed by mice with Nf1 knockout in boundary cap cells

Patients carrying an inactive NF1 allele develop tumours of Schwann cell origin called neurofibromas (NFs). Genetically engineered mouse models have significantly enriched our understanding of plexiform forms of NFs (pNFs). However, this has not been the case for cutaneous neurofibromas (cNFs), observed in all NF1 patients, as no previous model recapitulates their development. Here, we show that conditional Nf1 inactivation in Prss56-positive boundary cap cells leads to bona fide pNFs and cNFs. This work identifies subepidermal glia as a likely candidate for the cellular origin of cNFs, and provides insights on disease mechanisms, revealing a long, multistep pathological process in which inflammation play pivotal role. This new mouse model is an important asset for future clinical and therapeutic investigations of NF1-associated neurofibromas. Comparison between injured (14 days post-injury) versus uninjured skin isolated from Nf1-KO and control mice携带失活NF1等位基因的患者会罹患施万细胞（Schwann cell）起源的肿瘤，即神经纤维瘤（neurofibromas，NFs）。基因工程小鼠模型极大地丰富了我们对丛状神经纤维瘤（plexiform forms of NFs，pNFs）的认知。但针对所有NF1患者均会出现的皮肤神经纤维瘤（cutaneous neurofibromas，cNFs），这一局面却并未得到改观——此前尚无任何动物模型能够重现其发生发展过程。本研究证实，在Prss56阳性边界帽细胞中实现条件性Nf1基因失活，可诱导出真正的丛状神经纤维瘤与皮肤神经纤维瘤。本研究明确了表皮下胶质细胞是皮肤神经纤维瘤潜在的细胞起源，并揭示了相关疾病机制，证实其为一个漫长的多步骤病理过程，其中炎症发挥了关键调控作用。这一新型小鼠模型将为未来NF1相关神经纤维瘤的临床与治疗研究提供重要的研究资源。本研究对从Nf1基因敲除（Nf1-KO）小鼠及对照小鼠中分离得到的受伤（伤后14天）与未受伤皮肤样本开展了对比分析。