Lineage Reprogramming of Fibroblasts into Functional Neurons and Hepatocytes via Chemically Induced XEN-like State. Mus musculus

Small-molecule based lineage reprogramming has newly emerged as a promising approach for generating functional cell types. We recently found that the chemical induction of iPSCs from fibroblasts pass through an extra-embryonic endoderm (XEN)-like state. In this study, we demonstrated that these chemically-induced XEN-like cells were not restricted to be reprogrammed to iPSCs, but feasible to be induced into functional neurons, bypassing the pluripotent stage. These induced neurons possessed neuron-specific expression profiles, formed functional synapses in culture dish and further matured after transplantation into brains of adult mice. Notably, by using similar principles, hepatocytes could also be induced from the XEN-like cells. Furthermore, the XEN-like cells are highly expandable (for at least 20 passages), retaining genome stability and lineage specifying potentials. Our study establishes a featured route of chemical lineage reprogramming and may provide a universal platform for generating large amounts of diverse functional cell types via the expandable XEN-like state. Overall design: Total of 34 samples were analyzed, global transcriptional analysis of mouse fibroblasts, chemically-induced XEN-like cells, chemically-induced XEN-derived neuronal cells, chemically-induced XEN-derived hepatocyte-like cells, mouse primary neurons, mouse brain, mouse hepatocytes and mouse hepatic tissues by RNA-seq.