Transplantation of hMSCs Genome Edited with LEF1 Improves Cardio-Protective Effects in Myocardial Infarction
| Autor: | Je-Yoel Cho, Kang-Hoon Lee, Yiming Shen, Kyung-Sun Kang, Mincheol Choi, Hyunmin Cho, Pan Dong Ryu, Tae-Jin Shin |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Infarction medicine.disease_cause Article 03 medical and health sciences 0302 clinical medicine Fibrosis growth factors Drug Discovery LEF1 Medicine Myocardial infarction CRISPR/Cas9 Ejection fraction business.industry lcsh:RM1-950 Mesenchymal stem cell hUCB-MSCs medicine.disease cardio-protection Transplantation lcsh:Therapeutics. Pharmacology myocardial infarction 030104 developmental biology 030220 oncology & carcinogenesis embryonic structures Cancer research Molecular Medicine Stem cell business Oxidative stress |
| Zdroj: | Molecular Therapy. Nucleic Acids Molecular Therapy: Nucleic Acids, Vol 19, Iss, Pp 1186-1197 (2020) |
| ISSN: | 2162-2531 |
| DOI: | 10.1016/j.omtn.2020.01.007 |
| Popis: | 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 human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) stably expressing lymphoid enhancer-binding factor 1 (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 adeno-associated virus integration site 1 (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 proven 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 these 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. Keywords: LEF1, hUCB-MSCs, CRISPR/Cas9, myocardial infarction, cardio-protection, growth factors |
| Databáze: | OpenAIRE |
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