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Stem Cell Res Ther. 2018 Feb 26;9(1):51. doi: 10.1186/s13287-018-0803-7.

ISL1 overexpression enhances the survival of transplanted human mesenchymal stem cells in a murine myocardial infarction model.

Xiang Q1,2, Liao Y1,2, Chao H2, Huang W1,2, Liu J3, Chen H4, Hong D5, Zou Z1,2, Xiang AP1,2, Li W6,7.

Author information

1
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.
2
Zhongshan Medical School, Sun Yat-sen University, Guangzhou, People's Republic of China.
3
Department of Cardiology, the Red Cross hospital of Guangzhou City, the Fourth Affiliated Hospital of Jinan University, Guangzhou, People's Republic of China.
4
The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.
5
Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.
6
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.
7
Zhongshan Medical School, Sun Yat-sen University, Guangzhou, People's Republic of China. liweiq6@mail.sysu.edu.cn.

Abstract

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 1α promoter, which drives the expression of ISL1 (EF1α-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 H2O2 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.

KEYWORDS:

Human mesenchymal stem cells; ISL1; Myocardial infarction; Survival

PMID:
29482621
PMCID:
PMC5828309
DOI:
10.1186/s13287-018-0803-7
[Indexed for MEDLINE]
Free PMC Article

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