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

2.50
Hdl Handle:
http://hdl.handle.net/10033/317311
Title:
The temporal and hierarchical control of transcription factors-induced liver to pancreas transdifferentiation.
Authors:
Berneman-Zeitouni, Dana; Molakandov, Kfir; Elgart, Marina; Mor, Eytan; Fornoni, Alessia; Domínguez, Miriam Ramírez; Kerr-Conte, Julie; Ott, Michael; Meivar-Levy, Irit; Ferber, Sarah
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 glucagon 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 3(rd) 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.
Affiliation:
Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany; Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany
Citation:
The temporal and hierarchical control of transcription factors-induced liver to pancreas transdifferentiation. 2014, 9 (2):e87812 PLoS ONE
Journal:
PloS one
Issue Date:
2014
URI:
http://hdl.handle.net/10033/317311
DOI:
10.1371/journal.pone.0087812
PubMed ID:
24504462
Type:
Article
Language:
en
ISSN:
1932-6203
Appears in Collections:
publications of AG Cell and Gene therapy

Full metadata record

DC FieldValue Language
dc.contributor.authorBerneman-Zeitouni, Danaen
dc.contributor.authorMolakandov, Kfiren
dc.contributor.authorElgart, Marinaen
dc.contributor.authorMor, Eytanen
dc.contributor.authorFornoni, Alessiaen
dc.contributor.authorDomínguez, Miriam Ramírezen
dc.contributor.authorKerr-Conte, Julieen
dc.contributor.authorOtt, Michaelen
dc.contributor.authorMeivar-Levy, Iriten
dc.contributor.authorFerber, Sarahen
dc.date.accessioned2014-05-22T13:37:30Z-
dc.date.available2014-05-22T13:37:30Z-
dc.date.issued2014-
dc.identifier.citationThe temporal and hierarchical control of transcription factors-induced liver to pancreas transdifferentiation. 2014, 9 (2):e87812 PLoS ONEen
dc.identifier.issn1932-6203-
dc.identifier.pmid24504462-
dc.identifier.doi10.1371/journal.pone.0087812-
dc.identifier.urihttp://hdl.handle.net/10033/317311-
dc.description.abstractLineage-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 glucagon 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 3(rd) 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.en
dc.language.isoenen
dc.rightsArchived with thanks to PloS oneen
dc.titleThe temporal and hierarchical control of transcription factors-induced liver to pancreas transdifferentiation.en
dc.typeArticleen
dc.contributor.departmentGastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany; Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germanyen
dc.identifier.journalPloS oneen

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