The temporal and hierarchical control of transcription factors-induced liver to pancreas transdifferentiation.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
Domínguez, Miriam Ramírez
MetadataShow full item record
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.
CitationThe temporal and hierarchical control of transcription factors-induced liver to pancreas transdifferentiation. 2014, 9 (2):e87812 PLoS ONE
AffiliationGastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany; Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany
The following license files are associated with this item:
- PDX1, Neurogenin-3, and MAFA: critical transcription regulators for beta cell development and regeneration.
- Authors: Zhu Y, Liu Q, Zhou Z, Ikeda Y
- Issue date: 2017 Nov 2
- In vivo direct reprogramming of liver cells to insulin producing cells by virus-free overexpression of defined factors.
- Authors: Yang XF, Ren LW, Yang L, Deng CY, Li FR
- Issue date: 2017 Mar 31
- Long-term reversal of diabetes in non-obese diabetic mice by liver-directed gene therapy.
- Authors: Ren B, O'Brien BA, Byrne MR, Ch'ng E, Gatt PN, Swan MA, Nassif NT, Wei MQ, Gijsbers R, Debyser Z, Simpson AM
- Issue date: 2013 Jan
- Exendin-4 promotes liver cell proliferation and enhances the PDX-1-induced liver to pancreas transdifferentiation process.
- Authors: Aviv V, Meivar-Levy I, Rachmut IH, Rubinek T, Mor E, Ferber S
- Issue date: 2009 Nov 27
- PDGF Facilitates Direct Lineage Reprogramming of Hepatocytes to Functional β-Like Cells Induced by Pdx1 and Ngn3.
- Authors: Chang FP, Cho CH, Shen CR, Chien CY, Ting LW, Lee HS, Shen CN
- Issue date: 2016 Oct