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PMID:21108535

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Citation

Gefen-Halevi, S, Rachmut, IH, Molakandov, K, Berneman, D, Mor, E, Meivar-Levy, I and Ferber, S (2010) NKX6.1 promotes PDX-1-induced liver to pancreatic β-cells reprogramming. Cell Reprogram 12:655-64

Abstract

Reprogramming adult mammalian cells is an attractive approach for generating cell-based therapies for degenerative diseases, such as diabetes. Adult human liver cells exhibit a high level of developmental plasticity and have been suggested as a potential source of pancreatic progenitor tissue. An instructive role for dominant pancreatic transcription factors in altering the hepatic developmental fate along the pancreatic lineage and function has been demonstrated. Here we analyze whether transcription factors expressed in mature pancreatic β-cells preferentially activate β-cell lineage differentiation in liver. NKX6.1 is a transcription factor uniquely expressed in β-cells of the adult pancreas, its potential role in reprogramming liver cells to pancreatic lineages has never been analyzed. Our results suggest that NKX6.1 activates immature pancreatic markers such as NGN-3 and ISL-1 but not pancreatic hormones gene expression in human liver cells. We hypothesized that its restricted capacity to activate a wide pancreatic repertoire in liver could be related to its incapacity to activate endogenous PDX-1 expression in liver cells. Indeed, the complementation of NKX6.1 by ectopic PDX-1 expression substantially and specifically promoted insulin expression and glucose regulated processed hormone secretion to a higher extent than that of PDX-1 alone, without increasing the reprogrammed cells. This may suggest a potential role for NKX6.1 in promoting PDX-1 reprogrammed cells maturation along the β-cell-like lineage. By contrast, NKX6.1 repressed PDX-1 induced proglucagon gene expression. The individual and concerted effects of pancreatic transcription factors in adult extra-pancreatic cells, is expected to facilitate developing regenerative medicine approaches for cell replacement therapy in diabetics.

Links

PubMed Online version:10.1089/cell.2010.0030

Keywords

Adolescent; Adult; Animals; Biological Markers/metabolism; Cell Differentiation/physiology; Cell Lineage; Child; Child, Preschool; Glucagon/genetics; Glucagon/metabolism; Homeodomain Proteins/genetics; Homeodomain Proteins/metabolism; Humans; Insulin-Secreting Cells/cytology; Insulin-Secreting Cells/physiology; Liver/cytology; Trans-Activators/genetics; Trans-Activators/metabolism; Young Adult

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MESAU:NKX61

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MESAU:NKX61

involved_in

GO:0031016: pancreas development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MESAU:NKX61

involved_in

GO:0051594: detection of glucose

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MESAU:NKX61

involved_in

GO:0051091: positive regulation of DNA-binding transcription factor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MESAU:NKX61

involved_in

GO:0072560: type B pancreatic cell maturation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MESAU:NKX61

involved_in

GO:2000078: positive regulation of type B pancreatic cell development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MESAU:NKX61

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:PDX1

involved_in

GO:0003309: type B pancreatic cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:PDX1

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:PDX1

involved_in

GO:0051594: detection of glucose

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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