PMID- 23629003
OWN - NLM
STAT- MEDLINE
DCOM- 20140207
LR  - 20240104
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 21
IP  - 6
DP  - 2013 Jun
TI  - HLA engineering of human pluripotent stem cells.
PG  - 1232-41
LID - 10.1038/mt.2013.59 [doi]
AB  - The clinical use of human pluripotent stem cells and their derivatives is limited 
      by the rejection of transplanted cells due to differences in their human 
      leukocyte antigen (HLA) genes. This has led to the proposed use of 
      histocompatible, patient-specific stem cells; however, the preparation of many 
      different stem cell lines for clinical use is a daunting task. Here, we develop 
      two distinct genetic engineering approaches that address this problem. First, we 
      use a combination of gene targeting and mitotic recombination to derive 
      HLA-homozygous embryonic stem cell (ESC) subclones from an HLA-heterozygous 
      parental line. A small bank of HLA-homozygous stem cells with common haplotypes 
      would match a significant proportion of the population. Second, we derive HLA 
      class I-negative cells by targeted disruption of both alleles of the Beta-2 
      Microglobulin (B2M) gene in ESCs. Mixed leukocyte reactions and peptide-specific 
      HLA-restricted CD8(+) T cell responses were reduced in class I-negative cells 
      that had undergone differentiation in embryoid bodies. These B2M(-/-) ESCs could 
      act as universal donor cells in applications where the transplanted cells do not 
      express HLA class II genes. Both approaches used adeno-associated virus (AAV) 
      vectors for efficient gene targeting in the absence of potentially genotoxic 
      nucleases, and produced pluripotent, transgene-free cell lines.
FAU - Riolobos, Laura
AU  - Riolobos L
AD  - Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
FAU - Hirata, Roli K
AU  - Hirata RK
FAU - Turtle, Cameron J
AU  - Turtle CJ
FAU - Wang, Pei-Rong
AU  - Wang PR
FAU - Gornalusse, German G
AU  - Gornalusse GG
FAU - Zavajlevski, Maja
AU  - Zavajlevski M
FAU - Riddell, Stanley R
AU  - Riddell SR
FAU - Russell, David W
AU  - Russell DW
LA  - eng
GR  - DK55759/DK/NIDDK NIH HHS/United States
GR  - GM086497/GM/NIGMS NIH HHS/United States
GR  - P01 HL053750/HL/NHLBI NIH HHS/United States
GR  - R01 AI053193/AI/NIAID NIH HHS/United States
GR  - R01 CA114536/CA/NCI NIH HHS/United States
GR  - R01 GM086497/GM/NIGMS NIH HHS/United States
GR  - HL53750/HL/NHLBI NIH HHS/United States
GR  - R01 DK055759/DK/NIDDK NIH HHS/United States
GR  - AI053193/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20130430
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (HLA Antigens)
RN  - 0 (beta 2-Microglobulin)
SB  - IM
MH  - Alleles
MH  - CD8-Positive T-Lymphocytes/cytology/metabolism
MH  - Cell Differentiation
MH  - Cell Line
MH  - Cells, Cultured
MH  - Dependovirus/genetics
MH  - Embryonic Stem Cells/cytology/metabolism
MH  - Gene Targeting
MH  - Genetic Engineering
MH  - Genetic Vectors
MH  - HLA Antigens/*genetics/metabolism
MH  - Haplotypes
MH  - Histocompatibility/genetics
MH  - Homozygote
MH  - Humans
MH  - Pluripotent Stem Cells/*cytology/metabolism
MH  - Recombination, Genetic
MH  - beta 2-Microglobulin/genetics/metabolism
PMC - PMC3677304
EDAT- 2013/05/01 06:00
MHDA- 2014/02/08 06:00
PMCR- 2014/06/01
CRDT- 2013/05/01 06:00
PHST- 2013/05/01 06:00 [entrez]
PHST- 2013/05/01 06:00 [pubmed]
PHST- 2014/02/08 06:00 [medline]
PHST- 2014/06/01 00:00 [pmc-release]
AID - S1525-0016(16)32617-X [pii]
AID - 10.1038/mt.2013.59 [doi]
PST - ppublish
SO  - Mol Ther. 2013 Jun;21(6):1232-41. doi: 10.1038/mt.2013.59. Epub 2013 Apr 30.