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Transplantation of human mesenchymal stem cells genome-edited with LEF1 improves cardio-protective effects in myocardial infarction
Molecular Therapy - Nucleic Acids ( IF 5.919 ) Pub Date : 2020-01-18 , DOI: 10.1016/j.omtn.2020.01.007
Hyun-Min Cho; Kang-Hoon Lee; Yi-ming Shen; Tae-Jin Shin; Pan-Dong Ryu; Min-Cheol Choi; Kyung-Sun Kang; Je-Yoel Cho

Stem cell-based therapy is one of the most attractive approaches to ischemic heart diseases such as myocardial infarction (MI). We evaluated the cardio-protective effects of the hUCB-MSCs stably expressing LEF1 (LEF1/hUCB-MSCs) in a rat model of MI. LEF1 overexpression in hUCB-MSCs promoted cell proliferation and anti-apoptotic effects in hypoxic conditions. For the application of its therapeutic effects in vivo, the LEF1 gene was introduced into an AAVS1 locus known as a safe harbor site on chromosome 19 by CRISPR/Cas9-mediated gene integration in hUCB-MSCs. Transplantation of LEF1/hUCB-MSCs onto the infarction region in the rat model significantly improved overall survival. The cardio-protective effect of LEF1/hUCB-MSCs was proved by echocardiogram parameters including greatly improved left ventricle ejection fraction (EF) and fractional shortening (FS). Moreover, histology and immunohistochemistry successfully presented reduced MI region and fibrosis by LEF1/hUCB-MSCs. We found that this overall positive effects of LEF1/hUCB-MSCs are attributed by increased proliferation and survival of stem cells in oxidative stress conditions and by the secretion of various growth factors by LEF1. In conclusion, this study suggests that the stem cell-based therapy conjugated with genome editing of transcription factor LEF1, which promotes cell survival, could be an effective therapeutic strategy for cardiovascular disease.
更新日期:2020-01-21

 

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