Electrotaxis of cardiac progenitor cells, cardiac fibroblasts, and induced pluripotent stem cell-derived cardiac progenitor cells requires serum and is directed via PI3′K pathways

Abstract

Background The limited regenerative capacity of cardiac tissue has long been an obstacle to treating damaged myocardium. Cell-based therapy offers an enormous potential to the current treatment paradigms. However, the efficacy of regenerative therapies remains limited by inefficient delivery and engraftment. Electrotaxis, electrically guided cell movement, has been clinically utilized to improve recovery in a number of tissues, but has not been investigated for treating myocardial damage. Objectives The goal of the study is to test the electrotactic behaviors of several types of cardiac cells. Methods Cardiac Progenitor Cells (CPCs), Cardiac Fibroblasts (CFs), and human induced Pluripotent Stem cell-derived Cardiac Progenitor Cells (hiPSC-CPCs) were used. Results CPCs and CFs electrotax towards the anode of a direct current electric field (EF), while hiPSC-CPCs electrotax toward the cathode. The voltage-dependent electrotaxis of CPCs and CFs requires the presence of serum in the media. Addition of soluble vascular cell adhesion molecule (sVCAM) to serum-free media restores directed migration. We provide evidence that CPC and CF electrotaxis is mediated through phosphatidylinositide 3-kinases (PI3′K) signaling. In addition, Very Late Antigen-4 (VLA4), an integrin and growth factor receptor, is required for electrotaxis and localizes to the anodal edge of CPCs in response to direct current EF. HiPSC-derived CPCs do not express VLA4, migrate toward the cathode in a voltage-dependent manner, and similar to CPCs and CFs require media serum and PI3′K activity for electrotaxis. Conclusion The electrotactic behaviors of these therapeutic cardiac cells may be utilized for improving cell-based therapy for recovering function in damaged myocardium.

Enhanced Piezoelectric Fibered Extracellular Matrix to Promote Cardiomyocyte Maturation and Tissue Formation: A 3D Computational Model

“…The minimum intensity of the electric field ( ) is obtained for the PZE fiber with the minimum thickness ( ), and the maximum electric field ( ) is obtained for the PZE fiber with the highest thickness ( ). This range of electric fields is within the range of those that can be found in the bibliography [ 17 , 54 , 87 , 88 , 89 ]. In this way, it is possible to combine the mechanical and electrical stimulation of the cells, by tuning the imposed deformation on the PZE fiber with its thickness.…”

“…Furthermore, the migration velocity seems to be proportional to the intensity of the ES until a saturation point is reached, for which the velocity is maintained even with the increase in the ES [ 53 ]. B. Frederich et al observed that different cardiac cells show a proportional response to the electric field intensity [ 54 ]. Thus, we consider the electric forces, , due to the ES, proportional to the electric field, E , as [ 50 , 51 ] where E is the magnitude of the electric field.…”

“…Thus, we consider the electric forces, , due to the ES, proportional to the electric field, E , as [ 50 , 51 ] where E is the magnitude of the electric field. corresponds to the maximum electric field, which shows a saturation of the electrical stimuli [ 53 , 54 , 55 ]. is the cell surface charge density.…”

“…where E is the magnitude of the electric field. E sat corresponds to the maximum electric field, which shows a saturation of the electrical stimuli [53][54][55]. Ω is the cell surface charge density.…”

Expression of integrins to control migration direction of electrotaxis

“…EFs could redistribute integrin a5b1 toward the trailing edge in cathodal-migrating fibroblasts (63). It is also reported that integrin a4b1 is required for anodal electrotaxis and localizes to the front edge of cardiac progenitor cells (64). Integrin b1, one of the key subunits of integrin receptors, has been found to be involved in the electrotaxis by polarization and activation of several kinds of cells, including fibroblasts (65), epithelial cells (66), keratinocytes (67), and fish keratocytes (68).…”