PMID- 22685335
OWN - NLM
STAT- MEDLINE
DCOM- 20121210
LR  - 20220309
IS  - 1479-6805 (Electronic)
IS  - 0022-0795 (Linking)
VI  - 214
IP  - 3
DP  - 2012 Sep
TI  - In vivo studies on non-viral transdifferentiation of liver cells towards 
      pancreatic beta cells.
PG  - 277-88
AB  - Transdifferentiation in vivo is an attractive option for autologous replacement 
      of pancreatic beta cells in patients with type 1 diabetes. It has been achieved by 
      adenoviral delivery of genes for transcription factors in the liver and pancreas 
      of hyperglycaemic mice. However, these viral approaches are not clinically 
      applicable. We used the hydrodynamic approach to deliver genes Pdx1, Ngn3 
      (Neurog3) and MafA singly and in combination to livers of normoglycaemic rats. 
      Five expression plasmids were evaluated. Livers were removed 1, 3, 7, 14 and 28 
      days after gene delivery and assayed by quantitative PCR, semi-quantitative PCR 
      and immunohistology. Functional studies on hyperglycaemic rats were performed. 
      The highest and most sustained expression was from a CpG-depleted plasmid (pCpG) 
      and a plasmid with an in-frame scaffold/matrix attachment region ((pEPI(CMV)). 
      When Pdx1, Ngn3 and MafA were delivered together to normoglycaemic rats with 
      these plasmids, insulin mRNA was detected at all time points and was ~50-fold 
      higher with pCpG. Insulin mRNA content of livers at days 3 and 7 was equivalent 
      to that of a pancreas, with scattered insulin-positive cells detected by 
      immunohistology, but levels declined thereafter. Prohormone convertase 1/3 was 
      elevated at days 3 and 7. In hyperglycaemic rats, fasting blood glucose was lower 
      at days 1, 3 and 7 but not thereafter, and body weight was maintained to day 28. 
      We conclude that hydrodynamic gene delivery of multiple transcription factors to 
      rat liver can initiate transdifferentiation to pancreatic beta cells, but the 
      process is reversible and probably requires more sustained transcription factor 
      expression.
FAU - Cim, Abdullah
AU  - Cim A
AD  - Department of Hepatology and Transplantation, King's College London School of 
      Medicine, James Black Centre, London SE5 9NU, UK.
FAU - Sawyer, Greta J
AU  - Sawyer GJ
FAU - Zhang, Xiaohong
AU  - Zhang X
FAU - Su, Haibin
AU  - Su H
FAU - Collins, Louise
AU  - Collins L
FAU - Jones, Peter
AU  - Jones P
FAU - Antoniou, Michael
AU  - Antoniou M
FAU - Reynes, Jean-Paul
AU  - Reynes JP
FAU - Lipps, Hans-Joachim
AU  - Lipps HJ
FAU - Fabre, John W
AU  - Fabre JW
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120608
PL  - England
TA  - J Endocrinol
JT  - The Journal of endocrinology
JID - 0375363
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (Homeodomain Proteins)
RN  - 0 (Insulin)
RN  - 0 (Maf Transcription Factors, Large)
RN  - 0 (Mafa protein, mouse)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Neurog3 protein, mouse)
RN  - 0 (Trans-Activators)
RN  - 0 (pancreatic and duodenal homeobox 1 protein)
SB  - IM
MH  - Animals
MH  - Basic Helix-Loop-Helix Transcription Factors/genetics
MH  - Cell Differentiation/*genetics
MH  - Diabetes Mellitus, Experimental/therapy
MH  - Diabetes Mellitus, Type 1/*therapy
MH  - *Gene Transfer Techniques
MH  - Genetic Therapy/*methods
MH  - Homeodomain Proteins/genetics
MH  - Hyperglycemia/therapy
MH  - Insulin/metabolism
MH  - Insulin-Secreting Cells/*cytology/physiology
MH  - Liver/*cytology/physiology
MH  - Maf Transcription Factors, Large/genetics
MH  - Male
MH  - Nerve Tissue Proteins/genetics
MH  - Pancreas/cytology/physiology
MH  - Plasmids/genetics
MH  - Rats
MH  - Rats, Inbred Strains
MH  - Trans-Activators/genetics
MH  - Transcription, Genetic/genetics
EDAT- 2012/06/12 06:00
MHDA- 2012/12/12 06:00
CRDT- 2012/06/12 06:00
PHST- 2012/06/12 06:00 [entrez]
PHST- 2012/06/12 06:00 [pubmed]
PHST- 2012/12/12 06:00 [medline]
AID - JOE-12-0033 [pii]
AID - 10.1530/JOE-12-0033 [doi]
PST - ppublish
SO  - J Endocrinol. 2012 Sep;214(3):277-88. doi: 10.1530/JOE-12-0033. Epub 2012 Jun 8.