Article

Direct lineage conversion of terminally differentiated hepatocytes to functional neurons.

Institute for Stem Cell Biology and Regenerative Medicine and Department of Pathology, Stanford University School of Medicine, CA 94305, USA.
Cell stem cell (impact factor: 23.56). 09/2011; 9(4):374-82. DOI:10.1016/j.stem.2011.09.002
Source: PubMed

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.

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Keywords

binary lineage
 
contain neural
 
detectable epigenetic memory
 
different germ layers
 
donor transcriptome
 
fibroblast-
 
fibroblasts
 
genome-wide expression analyses
 
heterogeneous mesenchymal progenitor cells
 
human fibroblasts
 
induced neuronal
 
lineage reprogramming
 
lineages
 
neuronal transcriptional program
 
pluripotent intermediate state
 
recent studies
 
reprogramming factors lead
 
single-cell
 
terminally differentiated hepatocytes
 
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