Direct lineage reprogramming, including with small molecules, has emerged as a promising approach for generating desired cell types. We recently found that during chemical induction of induced pluripotent stem cells (iPSCs) from mouse fibroblasts, cells pass through an extra-embryonic endoderm (XEN)-like state. Here, we show that these chemically induced XEN-like cells can also be induced to directly reprogram into functional neurons, bypassing the pluripotent state. The induced neurons possess neuron-specific expression profiles, form functional synapses in culture, and further mature after transplantation into the adult mouse brain. Using similar principles, we were also able to induce hepatocyte-like cells from the XEN-like cells. Cells in the induced XEN-like state were readily expandable over at least 20 passages and retained genome stability and lineage specification potential. Our study therefore establishes a multifunctional route for chemical lineage reprogramming and may provide a platform for generating a diverse range of cell types via application of this expandable XEN-like state.

中文翻译：

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通过化学诱导的XEN样状态直接对成纤维细胞进行重编程。

直接谱系重编程，包括使用小分子，已经成为产生所需细胞类型的有前途的方法。我们最近发现，在化学诱导小鼠成纤维细胞诱导的多能干细胞（iPSC）的过程中，细胞会通过胚外内胚层（XEN）样状态。在这里，我们表明，这些化学诱导的XEN样细胞也可以被诱导直接重编程为功能性神经元，从而绕开了多能状态。诱导的神经元具有神经元特异性表达谱，在培养中形成功能性突触，并在移植到成年小鼠脑中后进一步成熟。使用类似的原理，我们还能够从XEN样细胞中诱导出肝细胞样细胞。处于诱导XEN样状态的细胞可以轻松扩增至少20代，并保留了基因组稳定性和谱系特异性潜力。因此，我们的研究建立了化学谱系重编程的多功能途径，并可能提供通过应用这种可扩展的XEN样状态生成多种细胞类型的平台。