Direct genesis of functional rodent and human Schwann cells from skin mesenchymal precursors (rat)

Recent reports of directed reprogramming have raised questions about the stability of cell lineages. Here, we have addressed this issue, focusing upon skin-derived precursors (SKPs), a dermally-derived precursor cell. We show by lineage tracing that murine SKPs from dorsal skin originate from mesenchymal and not neural crest-derived cells. These mesenchymally-derived SKPs can, without genetic manipulation, generate functional Schwann cells, a neural crest cell type, and are highly similar at the transcriptional level to Schwann cells isolated from the peripheral nerve. This is not a mouse-specific phenomenon, since human SKPs that are highly similar at the transcriptome level can be made from facial (neural crest-derived) and foreskin (mesodermally-derived) dermis, and the mesodermally-derived SKPs can make myelinating Schwann cells. Thus, non-neural crest-derived mesenchymal precursors can differentiate into bona fide peripheral glia in the absence of genetic manipulation, suggesting that developmentally-defined lineage boundaries are more flexible than widely thought.近期有关定向重编程（directed reprogramming）的研究报道引发了学界关于细胞谱系稳定性的广泛疑问。本研究聚焦于皮肤来源前体细胞（skin-derived precursors, SKPs）——一类真皮来源的前体细胞，针对该问题展开了系统性探讨。通过谱系示踪（lineage tracing）技术，我们证实：源自小鼠背部皮肤的SKPs起源于间质细胞，而非神经嵴细胞。这类间质来源的SKPs无需借助遗传操作，即可分化为具有功能的雪旺细胞（Schwann cells，一种神经嵴细胞类型），且其转录特征与外周神经分离得到的雪旺细胞在转录水平上高度相似。这一现象并非小鼠所特有：我们可分别从面部（神经嵴来源）与包皮（中胚层来源）真皮中获取在转录组水平上高度相似的人源SKPs，且其中中胚层来源的SKPs能够分化为有髓鞘雪旺细胞。综上，非神经嵴来源的间质前体细胞可在无遗传操作的情况下分化为真正的外周胶质细胞，这表明发育层面确定的谱系边界比学界普遍认知的更具灵活性。