Direct lineage conversion of terminally differentiated hepatocytes to functional neurons

Samuele Marro, Zhiping P. Pang, Nan Yang, Miao Chih Tsai, Kun Qu, Howard Y. Chang, Thomas C. Südhof, Marius Wernig

Research output: Contribution to journalArticlepeer-review

276 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)374-382
Number of pages9
JournalCell Stem Cell
Issue number4
StatePublished - Oct 4 2011
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Genetics
  • Cell Biology


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