PMID- 29482621 OWN - NLM STAT- MEDLINE DCOM- 20190110 LR - 20190110 IS - 1757-6512 (Electronic) IS - 1757-6512 (Linking) VI - 9 IP - 1 DP - 2018 Feb 26 TI - ISL1 overexpression enhances the survival of transplanted human mesenchymal stem cells in a murine myocardial infarction model. PG - 51 LID - 10.1186/s13287-018-0803-7 [doi] LID - 51 AB - BACKGROUND: The LIM-homeobox transcription factor islet-1 (ISL1) has been proposed as a marker for cardiovascular progenitor cells. This study investigated whether forced expression of ISL1 in human mesenchymal stem cells (hMSCs) improves myocardial infarction (MI) treatment outcomes. METHODS: The lentiviral vector containing the human elongation factor 1alpha promoter, which drives the expression of ISL1 (EF1alpha-ISL1), was constructed using the Multisite Gateway System and used to transduce hMSCs. Flow cytometry, immunofluorescence, Western blotting, TUNEL assay, and RNA sequencing were performed to evaluate the function of ISL1-overexpressing hMSCs (ISL1-hMSCs). RESULTS: The in vivo results showed that transplantation of ISL1-hMSCs improved cardiac function in a rat model of MI. Left ventricle ejection fraction and fractional shortening were greater in post-MI hearts after 4 weeks of treatment with ISL1-hMSCs compared with control hMSCs or phosphate-buffered saline. We also found that ISL1 overexpression increased angiogenesis and decreased apoptosis and inflammation. The greater potential of ISL1-hMSCs may be attributable to an increased number of surviving cells after transplantation. Conditioned medium from ISL1-hMSCs decreased the apoptotic effect of H(2)O(2) on the cardiomyocyte cell line H9c2. To clarify the molecular basis of this finding, we employed RNA sequencing to compare the apoptotic-related gene expression profiles of control hMSCs and ISL1-hMSCs. The results showed that insulin-like growth factor binding protein 3 (IGFBP3) was the only gene in ISL1-hMSCs with a RPKM value higher than 100 and that the difference fold-change between ISL1-hMSCs and control hMSCs was greater than 3, suggesting that IGFBP3 might play an important role in the anti-apoptosis effect of ISL1-hMSCs through paracrine effects. Furthermore, the expression of IGFBP3 in the conditioned medium from ISL1-hMSCs was almost fourfold greater than that in conditioned medium from control hMSCs. Moreover, the IGFBP3 neutralization antibody reversed the apoptotic effect of ISL1-hMSCs-CM. CONCLUSIONS: These results suggest that overexpression of ISL1 in hMSCs promotes cell survival in a model of MI and enhances their paracrine function to protect cardiomyocytes, which may be mediated through IGFBP3. ISL1 overexpression in hMSCs may represent a novel strategy for enhancing the effectiveness of stem cell therapy after MI. FAU - Xiang, Qiuling AU - Xiang Q AD - Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, People's Republic of China. AD - Zhongshan Medical School, Sun Yat-sen University, Guangzhou, People's Republic of China. FAU - Liao, Yan AU - Liao Y AD - Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, People's Republic of China. AD - Zhongshan Medical School, Sun Yat-sen University, Guangzhou, People's Republic of China. FAU - Chao, Hua AU - Chao H AD - Zhongshan Medical School, Sun Yat-sen University, Guangzhou, People's Republic of China. FAU - Huang, Weijun AU - Huang W AD - Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, People's Republic of China. AD - Zhongshan Medical School, Sun Yat-sen University, Guangzhou, People's Republic of China. FAU - Liu, Jia AU - Liu J AD - Department of Cardiology, the Red Cross hospital of Guangzhou City, the Fourth Affiliated Hospital of Jinan University, Guangzhou, People's Republic of China. FAU - Chen, Haixuan AU - Chen H AD - The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China. FAU - Hong, Dongxi AU - Hong D AD - Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China. FAU - Zou, Zhengwei AU - Zou Z AD - Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, People's Republic of China. AD - Zhongshan Medical School, Sun Yat-sen University, Guangzhou, People's Republic of China. FAU - Xiang, Andy Peng AU - Xiang AP AD - Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, People's Republic of China. AD - Zhongshan Medical School, Sun Yat-sen University, Guangzhou, People's Republic of China. FAU - Li, Weiqiang AU - Li W AD - Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, People's Republic of China. liweiq6@mail.sysu.edu.cn. AD - Zhongshan Medical School, Sun Yat-sen University, Guangzhou, People's Republic of China. liweiq6@mail.sysu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180226 PL - England TA - Stem Cell Res Ther JT - Stem cell research & therapy JID - 101527581 RN - 0 (Insulin-Like Growth Factor Binding Protein 3) RN - 0 (LIM-Homeodomain Proteins) RN - 0 (Transcription Factors) RN - 0 (insulin gene enhancer binding protein Isl-1) SB - IM MH - Animals MH - Cells, Cultured MH - Humans MH - Insulin-Like Growth Factor Binding Protein 3/metabolism MH - LIM-Homeodomain Proteins/*genetics/metabolism MH - *Mesenchymal Stem Cell Transplantation MH - Mesenchymal Stem Cells/cytology/*metabolism MH - Myocardial Infarction/*therapy MH - Myocytes, Cardiac/metabolism MH - Paracrine Communication MH - Rats MH - Rats, Sprague-Dawley MH - Transcription Factors/*genetics/metabolism PMC - PMC5828309 OTO - NOTNLM OT - Human mesenchymal stem cells OT - ISL1 OT - Myocardial infarction OT - Survival COIS- ETHICS APPROVAL: All the animal experiments involved in this research have been approved by the Ethics Committee, Zhongshan School of Medicine, Sun Yat-sen University (reference number: 2013 No. 40). All experimental research on animals followed internationally recognized guidelines, the Declaration of Helsinki, and all guidelines in China. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2018/02/28 06:00 MHDA- 2019/01/11 06:00 PMCR- 2018/02/26 CRDT- 2018/02/28 06:00 PHST- 2017/06/03 00:00 [received] PHST- 2018/02/08 00:00 [accepted] PHST- 2018/02/08 00:00 [revised] PHST- 2018/02/28 06:00 [entrez] PHST- 2018/02/28 06:00 [pubmed] PHST- 2019/01/11 06:00 [medline] PHST- 2018/02/26 00:00 [pmc-release] AID - 10.1186/s13287-018-0803-7 [pii] AID - 803 [pii] AID - 10.1186/s13287-018-0803-7 [doi] PST - epublish SO - Stem Cell Res Ther. 2018 Feb 26;9(1):51. doi: 10.1186/s13287-018-0803-7.