Induced pluripotent stem cells derived from mouse models of lysosomal storage disorders.
Most lysosomal storage diseases (LSDs) are life-threatening genetic diseases. The pathogenesis of these diseases is poorly understood. Induced pluripotent stem (iPS) cell technology offers new opportunities for both mechanistic studies and development of stem cell- based therapies. Here we report the generation of disease-specific iPS cells from mouse models of Fabry disease, globoid cell leukodystrophy (GLD), and mucopolysaccharidosis VII (MPSVII). These mouse model-derived iPS cells showed defects in disease-specific enzyme activities and significant accumulation of substrates for these enzymes. In the lineage-directed differentiation studies, Fabry-iPS and GLD-iPS cells were efficiently differentiated into disease-relevant cell types, such as cardiomyocytes and neural stem cells, which might be useful in mechanistic and therapeutic studies. Notably, MPSVII-iPS cells demonstrated a markedly impaired ability to form embryoid bodies (EBs) in vitro. MPSVII-EBs exibited elevated levels of hyaluronan and its receptor CD44, and markedly reduced expression levels of E-cadherin and cell-proliferating marker. Partial correction of enzyme deficiency in MSPVII-iPS cells led to improved EB formation and reversal of aberrant protein expression. These data indicate a potential mechanism for the partial lethality of MPSVII mice in utero, and suggest a possible abnormality of embryonic development in MPSVII patients. Thus, our study demonstrates the unique promise of iPS cells for studying the pathogenesis and treatment of LSDs.
Meng
Xing-Li
XL
Department of Gene Therapy, Jikei University School of Medicine, Tokyo 105-8461, Japan.
Shen
Jin-Song
JS
Kawagoe
Shiho
S
Ohashi
Toya
T
Brady
Roscoe O
RO
Eto
Yoshikatsu
Y
D000469:Alkaline Phosphatase; D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D000795:Fabry Disease / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000378:metabolism; D007150:Immunohistochemistry; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D007965:Leukodystrophy, Globoid Cell / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy; D051379:Mice; D016538:Mucopolysaccharidosis VII / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015820:Cadherins; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D000469:Alkaline Phosphatase
Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):2812-7
18287059
J Pediatr. 1982 Oct;101(4):574-6
6811712
Nature. 1995 Mar 23;374(6520):367-70
7885477
Nat Biotechnol. 2008 Jan;26(1):101-6
18059259
Annu Rev Med. 2006;57:283-96
16409150
Hum Genet. 1999 Jul-Aug;105(1-2):151-6
10480370
Stem Cells. 2005 Oct;23(9):1333-42
16081660
Cell. 2007 Nov 30;131(5):861-72
18035408
Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5856-61
18391196
Clin Chim Acta. 1992 Jan 31;205(1-2):87-96
1521344
Lab Invest. 1993 Jun;68(6):676-86
8515654
Cell. 1995 Oct 20;83(2):279-87
7585945
Cell. 2006 Aug 25;126(4):663-76
16904174
Mol Genet Metab. 2009 May;97(1):27-34
19217332
J Lab Clin Med. 1973 Dec;82(6):969-77
4202279
Science. 2007 Dec 21;318(5858):1920-3
18063756
J Pediatr. 1973 Feb;82(2):249-57
4265197
Proc Natl Acad Sci U S A. 1994 Aug 16;91(17):8263-7
8058792
J Biol Chem. 1978 Jan 10;253(1):184-90
201618
Birth Defects Res C Embryo Today. 2004 Mar;72(1):89-108
15054906
Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2540-4
9122231
Antioxid Redox Signal. 2007 Jun;9(6):623-52
17511580
J Inherit Metab Dis. 2004;27(3):385-410
15190196
Stem Cells. 2007 Sep;25(9):2224-34
17585171
Nat Protoc. 2007;2(12):3081-9
18079707
J Clin Invest. 2000 Aug;106(3):349-60
10930438
Gene Ther. 2000 Jun;7(12):1063-6
10871756
J Neurosci Res. 2003 Oct 15;74(2):266-77
14515356
Cell. 1980 Oct;21(3):927-34
6159985
Curr Opin Cell Biol. 1995 Dec;7(6):862-9
8608017
Mol Genet Metab. 2008 Nov;95(3):163-8
18707907
Pharmacol Ther. 2009 Apr;122(1):65-77
19318041
Pediatr Res. 2000 Jun;47(6):750-6
10832732
J Invest Dermatol. 2009 Jun;129(6):1412-20
19122650
JAMA. 1999 Jan 20;281(3):249-54
9918480