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

Abstract

Background: 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. Methods: 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. Results: 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 βcatenin 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 βcatenin. 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. Conclusions: 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.

Exploring a Chemotactic Role for EVs from Progenitor Cell Populations of Human Exfoliated Deciduous Teeth for Promoting Migration of Naïve BMSCs in Bone Repair Process

“…To detect the chemotactic ability of SHED-derived EVs, the chemotactic factors were investigated in the EV groups. It is acknowledged that TGF-β1 is one of the most important factors to drive MSC migration as well as IGF-1 [4,33]. Both factors were found in all EV groups in our study.…”

“…The process of natural bone repair is well organized and precisely controlled by numerous molecular signals. When a bone fracture occurs, a series of functional factors including platelet-derived growth factor (PDGF), transforming growth factor-β1 (TGF-β1), insulin-like growth factors (IGFs), and fibroblast growth factor-2 (FGF-2) is released into the extracellular space at the fracture site [3][4][5]. These factors collectively mediate the mobilization of bone marrow stromal cells (BMSCs), which proliferate and subsequently differentiate into osteoblasts to contribute to new bone formation.…”

Secreted Frizzled-Related Protein 2 and Extracellular Volume Fraction in Patients with Heart Failure

“…In our recently published study, we reported that in rat with acute myocardial infarction, transplantation of bone marrow mesenchymal stem cell overexpression insulin-like growth factor-1 greatly reduced infarct volume and myocardial fibrosis. These effects were mediated by the expression of SFRP2 [30]. Therefore, we propose that the association of SFRP2 and increased ECV fraction could be reflective of SFRP2 acting as a compensatory factor (rather than a risk factor) to counteract myocardial fibrosis during the development of HF.…”

Preconditioned and Genetically Modified Stem Cells for Myocardial Infarction Treatment

“…IGF-1 is another GF that was used to enhance the efficiency of stem cell therapy of MI. Lin and colleagues transplanted BMSCs overexpressing IGF-1 to rats with acute MI [ 83 ]. IGF-1 overexpressing BMSCs had higher survival and proliferation, protected cardiomyocytes from apoptosis, and reduced the infarct size.…”