Bradycardic mice undergo effective heart rate improvement after specific homing to the sino-atrial node and differentiation of adult muscle derived stem cells.

Pietro Mesirca, Daria Mamaeva, Isabelle Bidaud, Romain Davaze, Mattia L. DiFrancesco, Violeta Mitutsova, Angelo G. Torrente, Nikola Arsic, Joël Nargeot, Jörg Striessnig, Amy Lee, Ned J. Lamb, Matteo E. Mangoni, and Anne Fernandez

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Aug 24, 2018
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Received Date: 28th March 2018

Current treatment for heart automaticity disorders still lack a safe and efficient source of stem cells to bring about biological pacemaking. Since adult Muscle-Derived Stem Cells (MDSC) show multi-lineage differentiation in vitro including into spontaneously beating cardiomyocytes, we questioned whether MDSCs could effectively differentiate into cardiac pacemakers, a specific population of myocytes producing electrical impulses in the sino-atrial node of adult heart.  We show here that beating cardiomyocytes, differentiated from MDSC in vitro, exhibit typical characteristics of cardiac pacemakers: the expression of Hcn4, Tbx3 and Islet1, as well as spontaneous calcium transients and hyperpolarization-activated “funny” current, a unique signature of sino-atrial pacemakers. Pacemaker-like myocytes differentiated in vitro from Cav1.3 -deficient mouse MDSC produced slower Ca2+ transients, consistent with the reduction of native pacemaker activity in these mice. In vivo, systemic injection of undifferentiated wild type MDSCs into bradycardic mutant Cav1.3-/-  mice was ensued by their migration and homing to the sino-atrial node area within 48h and differentiation into Cav1.3 -expressing pacemaker-like myocytes within 10 days, a process accompanied by a significant improvement of the heart rate after 10 days that was maintained for up to 5 weeks. These findings identify MDSCs as directly transplantable stem cells that efficiently engraft, differentiate and improve heart rhythm in a mouse model of congenital bradycardia.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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