Function and Immunogenicity of Gene-corrected iPSC-derived Hepatocyte-Like Cells in Restoring Low Density Lipoprotein Uptake in Homozygous Familial Hypercholesterolemia View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-03-18

AUTHORS

Hirofumi Okada, Chiaki Nakanishi, Shohei Yoshida, Masaya Shimojima, Junichiro Yokawa, Masayuki Mori, Hayato Tada, Tsuyoshi Yoshimuta, Kenshi Hayashi, Tomoyoshi Yamano, Rikinari Hanayama, Masakazu Yamagishi, Masa-aki Kawashiri

ABSTRACT

Gene correction of induced pluripotent stem cells (iPSCs) has therapeutic potential for treating homozygous familial hypercholesterolemia (HoFH) associated with low-density lipoprotein (LDL) receptor (LDLR) dysfunction. However, few data exist regarding the functional recovery and immunogenicity of LDLR gene-corrected iPSC-derived hepatocyte-like cells (HLCs) obtained from an HoFH patient. Therefore, we generated iPSC-derived HLCs from an HoFH patient harbouring a point mutation (NM_000527.4:c.901 G > T) in exon 6 of LDLR, and examined their function and immunogenicity. From the patient’s iPSCs, one homozygous gene-corrected HoFH-iPSC clone and two heterozygous clones were generated using the CRISPR/Cas9 method. Both types of iPSC-derived HLCs showed recovery of the function of LDL uptake in immunofluorescence staining analysis. Furthermore, these gene-corrected iPSC-derived HLCs showed little immunogenicity against the patient’s peripheral blood mononuclear cells in a cell-mediated cytotoxicity assay. These results demonstrate that LDL uptake of iPSC-derived HLCs from HoFH can be restored by gene correction without the appearance of further immunogenicity, suggesting that gene-corrected iPSC-derived HLCs are applicable to the treatment of HoFH. More... »

PAGES

4695

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-019-41056-w

DOI

http://dx.doi.org/10.1038/s41598-019-41056-w

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1112857461

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30886174


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29 schema:description Gene correction of induced pluripotent stem cells (iPSCs) has therapeutic potential for treating homozygous familial hypercholesterolemia (HoFH) associated with low-density lipoprotein (LDL) receptor (LDLR) dysfunction. However, few data exist regarding the functional recovery and immunogenicity of LDLR gene-corrected iPSC-derived hepatocyte-like cells (HLCs) obtained from an HoFH patient. Therefore, we generated iPSC-derived HLCs from an HoFH patient harbouring a point mutation (NM_000527.4:c.901 G > T) in exon 6 of LDLR, and examined their function and immunogenicity. From the patient’s iPSCs, one homozygous gene-corrected HoFH-iPSC clone and two heterozygous clones were generated using the CRISPR/Cas9 method. Both types of iPSC-derived HLCs showed recovery of the function of LDL uptake in immunofluorescence staining analysis. Furthermore, these gene-corrected iPSC-derived HLCs showed little immunogenicity against the patient’s peripheral blood mononuclear cells in a cell-mediated cytotoxicity assay. These results demonstrate that LDL uptake of iPSC-derived HLCs from HoFH can be restored by gene correction without the appearance of further immunogenicity, suggesting that gene-corrected iPSC-derived HLCs are applicable to the treatment of HoFH.
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36 HoFH
37 HoFH patients
38 LDL
39 LDL uptake
40 LDLR
41 analysis
42 appearance
43 assays
44 blood mononuclear cells
45 cell-mediated cytotoxicity assay
46 cells
47 clones
48 correction
49 cytotoxicity assays
50 data
51 density lipoprotein uptake
52 dysfunction
53 exon 6
54 familial hypercholesterolemia
55 function
56 functional recovery
57 gene correction
58 genes
59 hepatocyte-like cells
60 heterozygous clones
61 homozygous familial hypercholesterolemia
62 hypercholesterolemia
63 immunofluorescence
64 immunogenicity
65 induced pluripotent stem cells
66 lipoprotein uptake
67 little immunogenicity
68 low-density lipoprotein uptake
69 method
70 mononuclear cells
71 mutations
72 patient induced pluripotent stem cells
73 patients
74 patients' peripheral blood mononuclear cells
75 peripheral blood mononuclear cells
76 pluripotent stem cells
77 point mutations
78 potential
79 receptor dysfunction
80 recovery
81 results
82 stem cells
83 therapeutic potential
84 treatment
85 treatment of HoFH
86 types
87 uptake
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