title: Direct lineage conversion of terminally differentiated hepatocytes to functional neurons.
abstract: Several recent studies have showed that mouse and human fibroblasts can be directly reprogrammed into induced neuronal (iN) cells, bypassing a pluripotent intermediate state. However, fibroblasts represent heterogeneous mesenchymal progenitor cells that potentially contain neural crest lineages, and the cell of origin remained undefined. This raises the fundamental question of whether lineage reprogramming is possible between cell types derived from different germ layers. Here, we demonstrate that terminally differentiated hepatocytes can be directly converted into functional iN cells. Importantly, single-cell and genome-wide expression analyses showed that fibroblast- and hepatocyte-derived iN cells not only induced a neuronal transcriptional program, but also silenced their donor transcriptome. The remaining donor signature decreased over time and could not support functional hepatocyte properties. Thus, the reprogramming factors lead to a binary lineage switch decision rather than an induction of hybrid phenotypes, but iN cells retain a small but detectable epigenetic memory of their donor cells.
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, CA 94305, USA.
authors.forename: Samuele
authors.initials: S
authors.lastname: Marro
authors.forename: Zhiping P
authors.initials: ZP
authors.lastname: Pang
authors.forename: Nan
authors.initials: N
authors.lastname: Yang
authors.forename: Miao-Chih
authors.initials: MC
authors.lastname: Tsai
authors.forename: Kun
authors.initials: K
authors.lastname: Qu
authors.forename: Howard Y
authors.initials: HY
authors.lastname: Chang
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
authors.forename: Marius
authors.initials: M
authors.lastname: Wernig
mesh_terms: D000418:Albumins / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D065150:Cellular Reprogramming / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D013997:Time Factors; D014158:Transcription, Genetic; D019076:Transgenes / Q000235:genetics
chemical_list: D000418:Albumins