Role of interleukin‐7 in fusion of rat bone marrow mesenchymal stem cells with cardiomyocytes in vitro and improvement of cardiac function in vivo

Abstract

Summary Aims Mesenchymal stem cells (MSCs) hold significant promise as potential therapeutic candidates following cardiac injury. However, to ensure survival of transplanted cells in ischemic environment, it is beneficial to precondition them with growth factors that play important role in cell survival and proliferation. Aim of this study is to use interleukin‐7 (IL‐7), a cell survival growth factor, to enhance the potential of rat bone marrow MSCs in terms of cell fusion in vitro and cardiac function in vivo. Methods Mesenchymal stem cells were transfected with IL‐7 gene through retroviral vector. Normal and transfected MSCs were co‐cultured with neonatal cardiomyocytes (CMs) and cell fusion was analyzed by flow cytometry and fluorescence microscopy. These MSCs were also transplanted in rat model of myocardial infarction (MI) and changes at tissue level and cardiac function were assessed by histological analysis and echocardiography, respectively. Results Co‐culture of IL‐7 transfected MSCs and CMs showed significantly higher (P < 0.01) number of fused cells as compared to normal MSCs. Histological analysis of hearts transplanted with IL‐7 transfected MSCs showed significant reduction (P < 0.001) in infarct size and better preservation (P < 0.001) of left ventricular wall thickness as compared to normal MSCs. Presence of cardiac‐specific proteins, α‐actinin, and troponin‐T showed that the transplanted MSCs were differentiated into cardiomyocytes. Echocardiographic recordings of the experimental group transplanted with transfected MSCs showed significant increase in the ejection fraction and fractional shortening (P < 0.01), and decrease in diastolic and systolic left ventricular internal diameters (P < 0.001) and end systolic and diastolic volumes (P < 0.01 and P < 0.001, respectively). Conclusion Interleukin‐7 is able to enhance the fusogenic properties of MSCs and improve cardiac function. This improvement may be attributed to the supportive action of IL‐7 on cell proliferation and cell survival contributing to the regeneration of damaged myocardium.

Mesenchymal Stem Cells for Regenerative Medicine

“…IGF-1-transfected MSCs protected the myocardium from fibrosis and cardiomyocyte apoptosis and reduced infarct size after myocardial infarction in rats [143]. Interleukin (IL)-7 enhances the fusion of MSCs with cardiomyocytes to improve cardiac function, with this attributed to the ability of IL-7 to promote cell proliferation and support damaged myocardial regeneration [144]. In addition to their ability to differentiate into cardiomyocytes, MSCs promoted angiogenesis by secreting vascular endothelial growth factor (VEGF) in a critical limb ischemia model [145], resulting in cardiac reconstruction.…”

Targeting cardiomyocyte proliferation as a key approach of promoting heart repair after injury

“…Although targeting cardiomyocyte proliferation is a hot topic of research in the field of regeneration, it was found that for cardiac regeneration, cell migration and mechanical changes in the cytoskeleton are also important [ 94 , 132 , 178 ]. Additionally, paracrine factors have a significant cofactor effect on cardiac regeneration after injury [ 163 , 173 ]. This reminds us that cardiac regeneration is a complex process that cannot be attributed to a single factor and a single cell type.…”

“…Subsequently, it was shown that IL-13 affected cell proliferation, apoptosis, and regeneration in neonatal mouse hearts by targeting ERK1/2 and Akt signaling [ 171 ]. Besides, several studies have shown that IL-4 is involved in regulating the proliferation of neonatal murine cardiomyocytes [ 172 ]; IL-7 can greatly enhance the cardiac function of MSCs transplantation and improve the heart morphology compared with only transplanted MSCs [ 173 ]; IL-15 also significantly protects cardiac function in mice after MI by reducing infarct size and promoting angiogenesis [ 174 ]. The above results demonstrate that the immune response affects cardiac regeneration.…”

Preconditioned and Genetically Modified Stem Cells for Myocardial Infarction Treatment

“…One study described the transduction of the IL-7 gene into MSCs and their subsequent transplantation into a rat model of MI. As a result, compared to standard MSCs, cells transduced with the IL-7 gene significantly reduced their infarct size and maintained the thickness of the left ventricular wall [ 78 ]. Similarly, the transplantation of MSCs overexpressing another cytokine, namely, IL-10, also improved their efficiency [ 79 ].…”