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

Sci Rep. 2019 Mar 18;9(1):4695. doi: 10.1038/s41598-019-41056-w.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Therapy / methods*
  • Cell Differentiation
  • Cell Line
  • Cells, Cultured
  • Cholesterol, LDL / metabolism
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Cytotoxicity, Immunologic
  • Genetic Therapy / methods*
  • Hepatocytes / cytology*
  • Hepatocytes / metabolism
  • Homozygote
  • Humans
  • Hyperlipoproteinemia Type II / genetics
  • Hyperlipoproteinemia Type II / immunology*
  • Induced Pluripotent Stem Cells / physiology*
  • Induced Pluripotent Stem Cells / transplantation
  • Lipoproteins, LDL / genetics
  • Lipoproteins, LDL / metabolism*
  • Mutation / genetics


  • Cholesterol, LDL
  • Lipoproteins, LDL