The temporal and hierarchical control of transcription factors-induced liver to pancreas transdifferentiation

Dana Berneman-Zeitouni, Kfir Molakandov, Marina Elgart, Eytan Mor, Alessia Fornoni, Miriam Ramírez Domínguez, Julie Kerr-Conte, Michael Ott, Irit Meivar-Levy, Sarah Ferber

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Abstract

Lineage-specific transcription factors (TFs) display instructive roles in directly reprogramming adult cells into alternate developmental fates, in a process known as transdifferentiation. The present study analyses the hypothesis that despite being fast, transdifferentiation does not occur in one step but is rather a consecutive and hierarchical process. Using ectopic expression of Pdx1 in human liver cells, we demonstrate that while glugacon and somatostatin expression initiates within a day, insulin gene expression becomes evident only 2-3 days later. To both increase transdifferentiation efficiency and analyze whether the process indeed display consecutive and hierarchical characteristics, adult human liver cells were treated by three pancreatic transcription factors, Pdx1, Pax4 and Mafa (3pTFs) that control distinct hierarchical stages of pancreatic development in the embryo. Ectopic expression of the 3pTFs in human liver cells, increased the transdifferentiation yield, manifested by 300% increase in the number of insulin positive cells, compared to each of the ectopic factors alone. However, only when the 3pTFs were sequentially supplemented one day apart from each other in a direct hierarchical manner, the transdifferentiated cells displayed increased mature β-cell-like characteristics. Ectopic expression of Pdx1 followed by Pax4 on the 2 nd day and concluded by Mafa on the 3rd day resulted in increased yield of transdifferentiation that was associated by increased glucose regulated c-peptide secretion. By contrast, concerted or sequential administration of the ectopic 3pTFs in an indirect hierarchical mode resulted in the generation of insulin and somatostatin co-producing cells and diminished glucose regulated processed insulin secretion. In conclusion transcription factors induced liver to pancreas transdifferentiation is a progressive and hierarchical process. It is reasonable to assume that this characteristic is general to wide ranges of tissues. Therefore, our findings could facilitate the development of cell replacement therapy modalities for many degenerative diseases including diabetes.

Original languageEnglish
Article numbere87812
JournalPLoS One
Volume9
Issue number2
DOIs
StatePublished - Feb 4 2014

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pancreas
Liver
Pancreas
Transcription Factors
transcription factors
Insulin
liver
Somatostatin
hepatocytes
somatostatin
insulin
cells
Glucose
c-peptide
Medical problems
Cell Transdifferentiation
Gene expression
glucose
insulin secretion
Cells

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Berneman-Zeitouni, D., Molakandov, K., Elgart, M., Mor, E., Fornoni, A., Domínguez, M. R., ... Ferber, S. (2014). The temporal and hierarchical control of transcription factors-induced liver to pancreas transdifferentiation. PLoS One, 9(2), [e87812]. https://doi.org/10.1371/journal.pone.0087812

The temporal and hierarchical control of transcription factors-induced liver to pancreas transdifferentiation. / Berneman-Zeitouni, Dana; Molakandov, Kfir; Elgart, Marina; Mor, Eytan; Fornoni, Alessia; Domínguez, Miriam Ramírez; Kerr-Conte, Julie; Ott, Michael; Meivar-Levy, Irit; Ferber, Sarah.

In: PLoS One, Vol. 9, No. 2, e87812, 04.02.2014.

Research output: Contribution to journalArticle

Berneman-Zeitouni, D, Molakandov, K, Elgart, M, Mor, E, Fornoni, A, Domínguez, MR, Kerr-Conte, J, Ott, M, Meivar-Levy, I & Ferber, S 2014, 'The temporal and hierarchical control of transcription factors-induced liver to pancreas transdifferentiation', PLoS One, vol. 9, no. 2, e87812. https://doi.org/10.1371/journal.pone.0087812
Berneman-Zeitouni, Dana ; Molakandov, Kfir ; Elgart, Marina ; Mor, Eytan ; Fornoni, Alessia ; Domínguez, Miriam Ramírez ; Kerr-Conte, Julie ; Ott, Michael ; Meivar-Levy, Irit ; Ferber, Sarah. / The temporal and hierarchical control of transcription factors-induced liver to pancreas transdifferentiation. In: PLoS One. 2014 ; Vol. 9, No. 2.
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