IGF-1 enhances BMSC viability, migration, and anti-apoptosis in myocardial infarction via secreted frizzled-related protein 2 pathway

• Published in: Stem cell research & therapy Vol. 11; no. 1; p. 22
• Main Authors: Lin, Mingzhuo, Liu, Xinyue, Zheng, Haoxiao, Huang, Xiaohui, Wu, Yu, Huang, Anqing, Zhu, Hailan, Hu, Yunzhao, Mai, Weiyi, Huang, Yuli
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 09.01.2020; BioMed Central; BMC
• Subjects: AKT protein; Animals; Apoptosis; Apoptosis - physiology; beta Catenin - metabolism; Bone marrow mesenchymal stem cell; Bone marrow transplantation; c-Myc protein; Camcorders; Cardiomyocytes; Cardiovascular diseases; Cell adhesion & migration; Cell culture; Cell migration; Cell Movement - physiology; Cell proliferation; Cell survival; Cell Survival - physiology; Cell viability; Cells, Cultured; Coronary artery disease; Cyclin D1; Diseases; Flow cytometry; Frizzled protein; Frizzled-related protein; Genes; Health aspects; Heart attack; Heart attacks; Heart cells; Heart diseases; Heart transplantation; Hypoxia; Insulin; Insulin-like growth factor I; Insulin-Like Growth Factor I - biosynthesis; Insulin-Like Growth Factor I - metabolism; Insulin-like growth factor-1; Insulin-like growth factors; Ischemia; Male; Membrane Proteins; Membranes; Mesenchymal Stem Cell Transplantation - methods; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - metabolism; Mesenchyme; Metabolism; Myc protein; Myocardial infarction; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocardial Infarction - therapy; Myocardial ischemia; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Sprague-Dawley; Secreted frizzled-related protein 2; Signal Transduction; Stem cell transplantation; Stem cells; Surgery; Transfection; China; Grand Island New York; United States > US; Japan; Myocardial infarction; Insulin-like growth factor-1; Bone marrow mesenchymal stem cell; Secreted frizzled-related protein 2
• ISSN: 1757-6512; 1757-6512
• DOI: 10.1186/s13287-019-1544-y

Bone marrow mesenchymal stem cell (BMSC) transplantation represents a promising therapeutic strategy for ischemic heart disease. However, its effects are hampered by the poor viability of transplanted cells and the hostile microenvironment of the ischemic region. Insulin-like growth factor-1 (IGF-1) is an important paracrine growth factor of BMSC and plays an important role in the properties of BMSC. Here, we investigated whether overexpressing IGF-1 could enhance the BMSC viability, migration, anti-apoptosis, and protective effects of cardiomyocytes, and explore the underlying mechanisms' focus on the role of the AKT/secreted frizzled-related protein 2 (SFRP2)/β-catenin pathway. We constructed BMSCs overexpressing insulin-like growth factor-1 (BMSCs-IGF-1) or empty vector (BMSCs-NC) using lentivirus, and evaluated cell survival, proliferation, and migration under normoxic and hypoxic conditions. Co-culture of rat cardiomyoblasts with BMSCs was performed to explore the paracrine effect of BMSCs-IGF-1 for rescuing cardiomyoblasts under hypoxia. Transplantation of BMSCs in acute myocardial infarction rats was used to explore the effect of BMSCs-IGF-1 therapy. BMSCs-IGF-1 exhibited a higher cell proliferation rate, migration capacity, and stemness, and were more resistant to apoptosis under hypoxia. Overexpression of IGF-1 upregulated the expression of total and nuclear β-catenin via the AKT-secreted frizzled-related protein 2 (SFRP2) pathway, which enhanced cell survival. Inhibition of AKT or SFRP2 knockdown by siRNA significantly antagonized the effect of IGF-1 and decreased the expression of β-catenin. The expression of β-catenin target genes, including cyclin D1 and c-Myc, were accordingly decreased. Moreover, BMSCs-IGF-1 could rescue cardiomyoblasts from hypoxia-induced apoptosis and preserve cell viability under hypoxia. Transplantation of BMSCs-IGF-1 into myocardial infarction rats greatly reduced infarct volume than BMSCs-NC, with significantly greater expression of SFRP2 and β-catenin. These results suggest that in BMSCs overexpressing IGF-1, SFRP2 is an important mediator for the enhancement of stem cell viability via activating, rather than antagonizing, the Wnt/β-catenin pathway.