Optogenetic Control of Heart Rhythm by Selective Stimulation of Cardiomyocytes Derived from Pnmt+ Cells in Murine Heart

Abstract

In the present study, channelrhodopsin 2 (ChR2) was specifically introduced into murine cells expressing the Phenylethanolamine n-methyltransferase (Pnmt) gene, which encodes for the enzyme responsible for conversion of noradrenaline to adrenaline. The new murine model enabled the identification of a distinctive class of Pnmt-expressing neuroendocrine cells and their descendants (i.e. Pnmt+ cell derived cells) within the heart. Here, we show that Pnmt+ cells predominantly localized to the left side of the adult heart. Remarkably, many of the Pnmt+ cells in the left atrium and ventricle appeared to be working cardiomyocytes based on their morphological appearance and functional properties. These Pnmt+ cell derived cardiomyocytes (PdCMs) are similar to conventional myocytes in morphological, electrical and contractile properties. By stimulating PdCMs selectively with blue light, we were able to control cardiac rhythm in the whole heart, isolated tissue preparations and single cardiomyocytes. Our new murine model effectively demonstrates functional dissection of cardiomyocyte subpopulations using optogenetics, and opens new frontiers of exploration into their physiological roles in normal heart function as well as their potential application for selective cardiac repair and regeneration strategies.

Optogenetic interrogation of integrin αVβ3 function in endothelial cells

“…In the past decade, there has been explosive growth in the use of optogenetics to study the mouse nervous system in vivo (Deisseroth, 2015). Optogenetic methodology is finding increasing use in cell biology (Grusch et al, 2014;Kim et al, 2016), and further advances in technology should enable the use of optogenetics in investigation of aspects of the cardiovascular system in model systems in vivo (Reade et al, 2017;Wang et al, 2017).…”

Cardiac neuroanatomy - Imaging nerves to define functional control

“…35 Their group have further evaluated the neural axis in the murine heart by identifying and stimulating a subpopulation of cardiomyocytes that bear the phenylethanolamine n-methyltransferase gene, which encodes the enzyme that converts norepinephrine to epinephrine, to exert control on heart rhythm through the use of optogenetics. 106 Wengrowski et al have shown photoactivation of cardiac sympathetic nerves affects cardiac electrical properties to increase heart rate along with cardiac contractile force (Figure 8). 97 To study the effects of vagal tone on exercise capacity, Machhada et al utilized a viral vector system to target neurons in the rat brainstem dorsal ventral motor nucleus, the main vagal nucleus in the central nervous system, with channelrhodopsin ChIEF.…”

Mechanical Characterization of hiPSC‐Derived Cardiac Tissues for Quality Control

“…First, cardiac patches should be fabricated with the appropriate dimensions, shape and cell contents for optimal repairing efficacy . Second, given that contractile force and beating frequency have been shown to be a good indicator whether postimplantation integration between the engineered tissue and the patient's heart is likely, the contractile forces and frequencies should be evaluated to ensure proper cardiac function upon integration with the damaged heart . Third, given that the intrinsic mechanical properties of the engineered cardiac tissues can be used to predict whether the tissues can sustain the stress during heart contraction during the implant‐heart integration process, the parameters such as elastic modulus, viscosity, shear modulus, bulk modulus, and dynamic stress distribution should be assessed to verify structural integrity …”