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Erschienen in: Inflammation 1/2019

13.08.2018 | ORIGINAL ARTICLE

Induced Expression of Endogenous CXCR4 in iPSCs by Targeted CpG Demethylation Enhances Cell Migration Toward the Ligand CXCL12

verfasst von: Can Jiang, Jun Guo, Huaiyan Cheng, Ying-Hong Feng

Erschienen in: Inflammation | Ausgabe 1/2019

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Abstract

Poor homing of cells after transplantation is an unresolved common issue in cardiac cell therapies. To enhance stem cell homing, the ligand CXC motif chemokine 12 (CXCL12) and its specific receptor CXC receptor type 4 (CXCR4) have been employed as a system in this study to show that induced expression of the endogenous CXCR4 gene in mouse-induced pluripotent stem cells (iPSCs) improved the cell migration. Loci-specific epigenome editing in the form of CpG demethylation at CXCR4 promoter region of the mouse iPSCs was accomplished with CXCR4b-TAL-Tet1c, chimeric fusion proteins of the catalytic domain of ten-eleven translocation 1 (TET1) to the C-terminal end of the DNA binding domains of predesigned synthetic transcription activator-like effectors (TALEs) that recognize specific DNA sequences within the mouse CXCR4 promoter region. Infection of the mouse iPSCs with the engineered CXCR4b-TAL-Tet1c in the form of lentiviral particles induced the loci-specific CpG demethylation and subsequent activation of CXCR4 expression in mouse iPSCs. As expected, the CXCR4-overexpressing iPSCs exhibited 3.9-fold greater migration than the control iPSCs did without alteration of the stemness and activated phosphorylation of AKT significantly. These results set a sound foundation for subsequent in vivo iPSCs transplantation studies in rodent models of acute myocardial infarction and heart failure. We show that TALEs can enhance the expression of CXCR4 by CpG methylation, and may retain the stemness. Migration of iPSCs activated by CXCL12 is associated with significant phosphorylation of AKT, not ERK1/2.
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Metadaten
Titel
Induced Expression of Endogenous CXCR4 in iPSCs by Targeted CpG Demethylation Enhances Cell Migration Toward the Ligand CXCL12
verfasst von
Can Jiang
Jun Guo
Huaiyan Cheng
Ying-Hong Feng
Publikationsdatum
13.08.2018
Verlag
Springer US
Erschienen in
Inflammation / Ausgabe 1/2019
Print ISSN: 0360-3997
Elektronische ISSN: 1573-2576
DOI
https://doi.org/10.1007/s10753-018-0869-5

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