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- 저자 : Oettgen, Peter (검색결과 1 건)
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Direct Conversion of Adult Skin Fibroblasts to Endothelial Cells by Defined Factors
Han, Jung-Kyu,Chang, Sung-Hwan,Cho, Hyun-Ju,Choi, Saet-Byeol,Ahn, Hyo-Suk,Lee, Jaewon,Jeong, Heewon,Youn, Seock-Won,Lee, Ho-Jae,Kwon, Yoo-Wook,Cho, Hyun-Jai,Oh, Byung-Hee,Oettgen, Peter,Park, Young-Ba American Heart Association 2014 Circulation Vol.130 No.14
<P><B>Background—</B></P><P>Cell-based therapies to augment endothelial cells (ECs) hold great therapeutic promise. Here, we report a novel approach to generate functional ECs directly from adult fibroblasts.</P><P><B>Methods and Results—</B></P><P>Eleven candidate genes that are key regulators of endothelial development were selected. Green fluorescent protein (GFP)–negative skin fibroblasts were prepared from Tie2-GFP mice and infected with lentiviruses allowing simultaneous overexpression of all 11 factors. Tie2-GFP<SUP>+</SUP> cells (0.9%), representing Tie2 gene activation, were detected by flow cytometry. Serial stepwise screening revealed 5 key factors (Foxo1, Er71, Klf2, Tal1, and Lmo2) that were required for efficient reprogramming of skin fibroblasts into Tie2-GFP<SUP>+</SUP> cells (4%). This reprogramming strategy did not involve pluripotency induction because neither Oct4 nor Nanog was expressed after 5 key factor transduction. Tie2-GFP<SUP>+</SUP> cells were isolated using fluorescence-activated cell sorting and designated as induced ECs (iECs). iECs exhibited endothelium-like cobblestone morphology and expressed EC molecular markers. iECs possessed endothelial functions such as <I>Bandeiraea simplicifolia</I>-1 lectin binding, acetylated low-density lipoprotein uptake, capillary formation on Matrigel, and nitric oxide production. The epigenetic profile of iECs was similar to that of authentic ECs because the promoters of VE-cadherin and Tie2 genes were demethylated. mRNA profiling showed clustering of iECs with authentic ECs and highly enriched endothelial genes in iECs. In a murine model of hind-limb ischemia, iEC implantation increased capillary density and enhanced limb perfusion, demonstrating the in vivo viability and functionality of iECs.</P><P><B>Conclusions—</B></P><P>We demonstrated the first direct conversion of adult fibroblasts to functional ECs. These results suggest a novel therapeutic modality for cell therapy in ischemic vascular disease.</P>
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