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

Abstract

BackgroundThe 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.MethodsThe 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).ResultsThe 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-0803-7) contains supplementary material, which is available to authorized users.

Fate Tracing of Isl1+Cells in Adult Mouse Hearts under Physiological and Exercise Conditions

“…Tamoxifen-induced Cre/ loxP recombinant cells were detected in the heart sinoatrial node, cardiac ganglia, aortic arch, and pulmonary roots in Isl1-CreERT/Ro-sa26-lacZ adult mice (▶Fig. 1b), consistent with previous results [5,23,24]. The expression of CreERT2 cells in these tissues was further confirmed by using X-gal staining in frozen and paraffin-embedded sections of heart tissues from heterozygote ( ▶Fig.…”

Mapping Trends and Identifying Hotspots in Research on Mesenchymal Stem Cells in Cardiovascular Disease

“…Sun Yat-sen University researched the effects of exons (Exo) [50], the TGF-β superfamily [51], the long noncoding RNA brave heart (lncRNA-Bvht) [52], apelin [53] and granulocyte colony stimulating factor (G-CSF) [54] on the proliferation, differentiation and vascularization of MSCs. The functions of the transcription factors islet-1 (ISL1) [55] and platelet brin (PRF) [56] in regulating the repair of myocardial infarction by MSCs have been explored. Although basic research on cardiovascular stem cells in China is at the forefront of efforts around the world, progress on clinical studies in China is stagnant, which may be related to the lack of e cient scienti c approval systems and strict regulatory policies.…”

“…Reviews ranked second, as there were 755 reviews, accounting for 22.900% of the total. The other 8 document types were meeting abstracts (98), editorial materials (55), book chapters (35), proceedings papers (32), early access (20), letters (5), corrections (3) and news items (1). VOSviewer constructs a map based on the cooccurrence matrix.…”

Genetic Engineering as a Strategy to Improve the Therapeutic Efficacy of Mesenchymal Stem/Stromal Cells in Regenerative Medicine

“…MSCs overexpressing Follistatin-like 1, a pro-survival cardiokine for cardiomyocytes, had increased survival, proliferation and engraftment, thereby improving in about 2-fold their therapeutic efficacy when compared to mcherry transgenic control MSCs in a myocardial infarction model ( Shen et al, 2019 ). Similarly, overexpression of Islet-1, a transcription factor involved in cardiogenesis regulation and a marker of cardiovascular progenitor cells, promoted MSCs survival post-transplant and enhanced their paracrine function ( Xiang et al, 2018 ).…”