Establishment of an induced pluripotent stem cell based model of transthyretin cardiac amyloidosis

Introduction Myocardial deposition of amyloid fibers composed of transthyretin (TTR) misfolded monomers causes TTR-related amyloidosis (ATTR) cardiomyopathy. Pre-clinical human-derived disease models are necessary for the study of the pathophysiology and novel therapies against ATTR cardiomyopathy. Method Human induced pluripotent stem cells (hiPSC) were created from two patients suffered from familial ATTR cardiomyopathy carrying Gly67Glu and Ala117Ser mutation, respectively. In-vitro models of ATTR cardiomyopathy were created by culturing the hiPSC-derived cardiomyocytes (iCM) with the conditioned medium derived from their corresponding hiPSCs derived hepatocytes-like cells (iHep), and the therapeutic effect of epigallocatechin gallate (EGCG) was investigated. RNA sequencing was used to investigate the pathophysiological changes and the therapeutic actions of EGCG in ATTR cardiomyopathy. Results The mutant TTR secreted by the iHep with TTR gene mutations resulted in increased TTR depositions on the iCMs which exhibited impaired contractile function and abnormal calcium transient. Moreover, increased unfolded protein response (UPS) and oxidative stress with autophagy impairment were observed in iCMs exposed to mutant TTR. Treatment with 1mM EGCG reduced amyloid deposition, reversed the abnormal electromechanical coupling, and alleviated the activation of UPS and oxidative stress, and improved autophagy in iCMs exposed to mutant TRR. Conclusion Our in-vitro iPSC-derived dual-cell model provided insights on the pathogenic mechanisms and drug testing. It demonstrated ATTR results in increased UPS and oxidative stress, and impairment of autophagy in ATTR cardiomyopathy.