IGF1 and NRG1 Enhance Proliferation, Metabolic Maturity, and the Force-Frequency Response in hESC-Derived Engineered Cardiac Tissues

Received May 17, 2017; Accepted Jul 25, 2017

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1. Introduction

The development of defined methods to derive cardiomyocytes from human pluripotent stem cells (hPSCs) has provided a valuable platform to develop regenerative medicine technologies. Cardiomyocytes derived from human embryonic stem cells (hESC-cardiomyocytes) and tissues constructed from them have been shown to exhibit a cardiac phenotype characterized by gene expression patterns, electrophysiological behavior, and mechanical function. Previous research describes the response of engineered cardiac tissues (ECTs) to common drugs; however, little is known about how ECTs develop under in utero-like biochemical conditions. Just as embryonic development has informed directed differentiation of hESCs to the cardiac lineage, we hypothesize that fetal development can inform how ECTs grow and mature. In order for ECTs to advance towards the clinical realm as both a translational therapy and an in vitro model, a more thorough understanding of how to manipulate hESC-cardiomyocyte maturation in 3D tissues via developmental cues is required.

Two growth factors crucial to cardiac development in vivo are insulin-like growth factor 1 (IGF1) and neuregulin-1β (NRG1). IGF1 has been implicated in physiological growth of the heart, and studies performed to downregulate [1] and upregulate [2] its receptor in mouse models show dilated cardiomyopathy and cardiomyocyte physiological hypertrophy, respectively. At the cellular level, IGF1 has been shown to increase proliferation in hESC-cardiomyocytes via the PI 3-kinase/Akt pathway in vitro [3]. Thus, carefully regulated IGF1 signaling is required for proper development and maturation of the heart in order to achieve both cardiomyocyte proliferation and growth, yet the timing of IGF1 stimulation likely alters this response. Similarly, a critical need for appropriate NRG1 signaling during development has been demonstrated. When NRG1 [4] or its receptors ErbB2 [5] and ErbB4 [6] are deleted in mice, ventricular trabeculation and endocardial cushion formation are depressed, and mice die midembryogenesis. When mice embryos are cultured ex vivo, NRG1 is required for complete...