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Tbx18 Transcription Factor Overexpression in Human-Induced Pluripotent Stem Cells Increases Their Differentiation Into Pacemaker-Like Cells Publisher Pubmed



Gorabi AM1 ; Hajighasemi S2 ; Tafti HA3 ; Atashi A4 ; Soleimani M5 ; Aghdami N6 ; Saeid AK7 ; Khori V8 ; Panahi Y9 ; Sahebkar A10, 11, 12
Authors
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Authors Affiliations
  1. 1. Department of Basic and Clinical Research, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
  2. 2. Department of Medical Biotechnology, Faculty of Paramedicine, Qazvin University of Medical Sciences, Qazvin, Iran
  3. 3. Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  4. 4. Stem Cell and Tissue Engineering Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
  5. 5. Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
  6. 6. Department of Regenerative Biomedicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Tehran, Iran
  7. 7. Department of Cardiology, Tehran University of Medical Science, Tehran, Iran
  8. 8. Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
  9. 9. Pharmacotherapy Department, School of Pharmacy, Baqiyatallah University of Medical Sciences, Tehran, Iran
  10. 10. Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
  11. 11. Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
  12. 12. School of Pharmacy, Mashhad University of Medical Sciences, Tehran, Iran

Source: Journal of Cellular Physiology Published:2019


Abstract

Background: The discovery of gene- and cell-based strategies has opened a new area to investigate novel approaches for the treatment of many conditions caused by cardiac cell failure. The TBX18 (T-box 18) transcription factor is considered as a prominent factor in the sinoatrial node (SAN) formation during the embryonic development. In this in vitro study, the effect of TBX18 gene expression on human-induced pluripotent-stem-cell-derived cardiomyocytes (hiPS-CMs) to induce pacemaker-like cells was examined. Methods: The human-dermal-fibroblast-derived iPSCs were transfected using chemical, physical, and Lentiviral methods of TBX18 gene delivery during differentiation into cardiomyocytes (CMs). After the differentiation process through small-molecule-based temporal modulation of the Wnt signaling pathway, the hiPSC-CMs were analyzed using the real-time polymerase chain reaction, immunocytochemistry, immunofluorescence, whole-cell patch-clamp recording, and western blotting to investigate the accuracy of differentiation and identify the effect exerted by TBX18. Results: The hiPS-CMs showed spontaneous beating and expressed specific markers of cardiac cells. The lentiviral-mediated TBX18 delivery was the most efficient method for transfection. The results showed the increment in Connexin 43 expression among untransfected hiPS-CMs, whereas this protein was significantly downregulated followed by TBX18 overexpression. TBX18-hiPSCMs were detected with pacemaker cell features. Conclusions: It was demonstrated that the TBX18 gene is able to conduct hiPSCs to differentiate into pacemaker-like cells. The TBX18 gene delivery seems to have the potential for the development of biological pacemakers; however, more investigations are still needed to assess its usefulness to fix arrhythmic conditions with SAN failure basis. © 2018 Wiley Periodicals, Inc.
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