Tissue-Specific Stem Cells Obtained by Reprogramming of Non-Obese Diabetic (NOD) Mouse-Derived Pancreatic Cells Confer Insulin Production in Response to Glucose.
Type 1 diabetes occurs due to the autoimmune destruction of pancreatic β-cells in islets. Transplantation of islets is a promising option for the treatment of patients with type 1 diabetes that experience hypoglycemic unawareness despite maximal care, but the present shortage of donor islets hampers such transplantation. Transplantation of insulin-producing cells derived from the patients themselves would be one of the most promising approaches to cure type 1 diabetes. Previously, we demonstrated that insulin-producing cells could be produced by transfecting murine pancreatic cells with Yamanaka's reprogramming factors. Non-obese diabetic (NOD) mice are naturally occurring mutant mice defective in insulin production due to autoimmune ablation of pancreatic β-cells. In this study, we showed that glucose-sensitive insulin-producing cells are successfully generated by transfecting primary pancreatic cells from NOD mice (aged 6 months old) with a plasmid harboring the cDNAs for Oct-3/4, Sox2, Klf4, and c-Myc. Transfection was repeated 4 times in a 2 day-interval. Sixty-five days after final transfection, cobblestone-like colonies appeared. They proliferated in vitro and expressed pluripotency-related genes as well as Pdx1, a transcription factor specific to tissue-specific stem cells for the β-cell lineage. Transplantation of these cells into nude mice failed to produce teratoma unlike induced pluripotent stem cells (iPSCs). Induction of these cells to the pancreatic β-cell lineage demonstrated their capability to produce insulin in response to glucose. These findings suggest that functional pancreatic β-cells can be produced from patients with type 1 diabetes. We call these resultant cells as "induced tissue-specific stem cells from the pancreas" (iTS-P) that could be valuable sources of safe and effective materials for cell-based therapy in type 1 diabetes.
Division of Pediatric Dentistry, Graduate School of Medical and Dental Science, Niigata University, Niigata, 951-8514, Japan.
Issei
I
Saitoh
Section of Gene Expression Regulation, Frontier Science Research Center, Kagoshima University, Kagoshima, 890-0065, Japan.
Masahiro
M
Sato
Division of Pediatric Dentistry, Graduate School of Medical and Dental Science, Niigata University, Niigata, 951-8514, Japan.
Miki
M
Soda
Department of Pediatric Dentistry, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, 890-8544, Japan.
Emi
E
Inada
Division of Pediatric Dentistry, Graduate School of Medical and Dental Science, Niigata University, Niigata, 951-8514, Japan.
Yoko
Y
Iwase
Division of Pediatric Dentistry, Graduate School of Medical and Dental Science, Niigata University, Niigata, 951-8514, Japan.
Tomoya
T
Murakami
Division of Anatomy and Cell Biology of the Hard Tissue, Niigata University Graduate School of Medical and Dental Sciences, Niigata University, Niigata, 951-8514, Japan.
Hayato
H
Ohshima
Division of Pediatric Dentistry, Graduate School of Medical and Dental Science, Niigata University, Niigata, 951-8514, Japan.
Haruaki
H
Hayasaki
Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyu, Okinawa, 903-0215, Japan.
Hirofumi
H
Noguchi
Cell Stem Cell. 2007 Jun 7;1(1):39-49
18371333
Science. 2007 Dec 21;318(5858):1920-3
18063756
Nature. 2007 Jul 19;448(7151):313-7
17554338
Stem Cells Transl Med. 2014 Jan;3(1):114-27
24292793
Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):157-62
19109433
Diabetologia. 2004 Oct;47(10):1650-6
15490110
Nat Med. 2004 Mar;10(3):305-9
14770176
Cell Stem Cell. 2009 Jun 5;4(6):513-24
19427283
Nat Genet. 2007 Mar;39(3):295-302
17325680
Development. 2009 Feb;136(4):509-23
19168672
Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15768-73
19720998
Nat Genet. 2009 Dec;41(12):1350-3
19881528
Nat Biotechnol. 2006 Nov;24(11):1392-401
17053790
J Biol Chem. 2008 Nov 14;283(46):31601-7
18782754
Cell. 2006 Aug 25;126(4):663-76
16904174
Transplant Proc. 2008 Mar;40(2):422-3
18374088
Nat Biotechnol. 2008 Mar;26(3):313-5
18278034
Science. 2007 Dec 21;318(5858):1917-20
18029452
Nat Immunol. 2009 Feb;10(2):129-32
19148193
Nat Biotechnol. 2005 Jul;23(7):857-61
16003374
Diabetes. 1998 Mar;47(3):482-6
9519758
Endocr J. 2007 Feb;54(1):7-16
17053295
Cell Stem Cell. 2011 Jul 8;9(1):17-23
21726830
Nature. 2009 Aug 27;460(7259):1136-9
19668188
N Engl J Med. 2000 Jul 27;343(4):230-8
10911004
Nat Biotechnol. 2008 Apr;26(4):443-52
18288110
Cell Death Differ. 2015 Jan;22(1):145-55
25190146
Cell Stem Cell. 2009 Feb 6;4(2):95-6
19200794
Cell Stem Cell. 2009 Feb 6;4(2):141-54
19200803
Nature. 2011 Mar 3;471(7336):68-73
21289626
Cell. 2007 Nov 30;131(5):861-72
18035408
Ann N Y Acad Sci. 2007 Apr;1103:1-10
17376838
Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5856-61
18391196
Nature. 2010 Sep 16;467(7313):285-90
20644535
Nat Cell Biol. 2011 May;13(5):541-9
21499256
Cell Transplant. 2009;18(5):563-71
19775518
Nat Biotechnol. 2010 Aug;28(8):848-55
20644536
Nature. 2010 Mar 11;464(7286):292-6
20164838
Cell. 2008 Sep 5;134(5):877-86
18691744