Electrotaxis of Cardiac Progenitor Cells, Cardiac Fibroblasts, and induced Pluripotent Stem cell‐derived Cardiac Progenitor Cells requires serum and is directed via PI3K pathways
Authors: Frederich Bert Joseph , Timofeyev Valeriy , Thai Phung N , Lau Victor C , Sirish Padmini , Chiamvimonvat Nipavan 
Published: November 2023

Cardiovascular disease is the largest cause of mortality in the world. Specifically, in the United States, 1 in 6 people suffer from coronary artery disease, which increases their risk of heart attacks. Heart attacks can result in ischemic damage to heart tissue which is often irreversible. New cell‐based therapies are being researched for improving tissue recovery; however, these therapies are limited by difficulties in targeting these cells to site of damage. By learning more about how these cells move, we can identify new and more effective methods for directing therapeutic cardiac cell movement to damaged cardiovascular tissues, improving heart function.Electrotaxis, electrical stimulation to guide cell movement, has been clinically utilized to improve recovery in a number of tissues but it has not been researched for treating heart attacks. Gaining a better understanding of the electrotaxis mechanisms of therapeutic cardiac cells is especially important for improving the efficacy of current cell‐based therapies for improving recovery from heart attacks.Here we report several types of clinically relevant cardiac cells that exhibit novel electrotactic behaviors. Cardiac Progenitor Cells (CPCs) and Cardiac Fibroblasts (CFs) electrotax towards the anode of a direct current electric field, while induced Pluripotent Stem cell‐derived Cardiac Progenitor Cells (iPS‐CPCs) electrotax toward the cathode. The voltage‐dependent electrotaxis of CPCs and CFs requires the presence of serum in the media but addition of soluble vascular cell adhesion molecule (sVCAM) to serum‐free media restores directed migration. We further present evidence that CPC and CF electrotaxis is mediated through phosphatidylinositide 3‐kinases (PI3'K) signaling, a pathway often involved in cell migration.We have also found that Very Late Antigen‐4 (VLA4), an integrin and growth factor receptor, is required for voltage‐dependent electrotaxis and localizes to the anodal edge of CPCs in response to direct current electric field. This anodal localization of VLA4 occurs even in the absence of serum in the media, a media condition that does not allow for directed cell movement.iPS‐CPCs which are iPSCs differentiated into CPCs that do not express VLA4, migrate cathodally in a voltage‐dependent manner, and similarly to CPCs and CFs still require media serum, and PI3'K activity for electrotaxis.We have described the novel electrotactic behavior of CPCs, CFs, and iPS‐CPCs and identified a molecular mechanism for CPC and CF electrotactic migration. The electrotaxis of these cardiac cell types shows the importance of electrical fields on the localization of cardiac cells. Further understanding of the underlying mechanisms for the electroxis in these therapeutic cells would allow for the development of better treatments based on combined cellular, molecular, and electrical interventions for improving heart function.Support or Funding InformationThis work was supported by NIH R01 HL085727, R01 HL085844, and the VA Merit Review Grant I01 BX000576 to NC, Postdoctoral Fellowship award to PS from NIH T32 Training Grant in Basic and Translational Medicine (NIH HL08350) and California Institute for Regenerative Medicine, Stem Cell Training Program (TG2‐01163).