Programming and isolation of highly pure physiologically and pharmacologically functional sinus-nodal bodies from pluripotent stem cells

Stem Cell Reports. 2014 Apr 17;2(5):592-605. doi: 10.1016/j.stemcr.2014.03.006. eCollection 2014 May 6.

Abstract

Therapeutic approaches for "sick sinus syndrome" rely on electrical pacemakers, which lack hormone responsiveness and bear hazards such as infection and battery failure. These issues may be overcome via "biological pacemakers" derived from pluripotent stem cells (PSCs). Here, we show that forward programming of PSCs with the nodal cell inducer TBX3 plus an additional Myh6-promoter-based antibiotic selection leads to cardiomyocyte aggregates consisting of >80% physiologically and pharmacologically functional pacemaker cells. These induced sinoatrial bodies (iSABs) exhibited highly increased beating rates (300-400 bpm), coming close to those found in mouse hearts, and were able to robustly pace myocardium ex vivo. Our study introduces iSABs as highly pure, functional nodal tissue that is derived from PSCs and may be important for future cell therapies and drug testing in vitro.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Clocks
  • Calcium / metabolism
  • Cell Differentiation
  • Cell Line
  • Cellular Reprogramming*
  • Coculture Techniques
  • In Vitro Techniques
  • Mice
  • Models, Biological
  • Myocytes, Cardiac / metabolism
  • Myosin Heavy Chains / genetics
  • Myosin Heavy Chains / metabolism
  • Patch-Clamp Techniques
  • Pluripotent Stem Cells / cytology*
  • Pluripotent Stem Cells / metabolism
  • Sick Sinus Syndrome / metabolism
  • Sick Sinus Syndrome / pathology
  • Sick Sinus Syndrome / veterinary
  • Sinoatrial Node / cytology
  • Sinoatrial Node / physiology*
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism

Substances

  • Myh6 protein, mouse
  • T-Box Domain Proteins
  • Tbx3 protein, mouse
  • Myosin Heavy Chains
  • Calcium