ERRγ agonist under mechanical stretching manifests hypertrophic cardiomyopathy phenotypes of engineered cardiac tissue through maturation.

Engineered cardiac tissue (ECT) using human induced pluripotent stem cell-derived cardiomyocytes is a promising tool for modeling heart disease. However, tissue immaturity makes robust disease modeling difficult. Here, we established a method for modeling hypertrophic cardiomyopathy (HCM) malignant (MYH7 R719Q) and nonmalignant (MYBPC3 G115 ^∗ ) pathogenic sarcomere gene mutations by accelerating ECT maturation using an ERRγ agonist, T112, and mechanical stretching. ECTs treated with T112 under 10% elongation stimulation exhibited more organized and mature characteristics. Whereas matured ECTs with the MYH7 R719Q mutation showed broad HCM phenotypes, including hypertrophy, hypercontraction, diastolic dysfunction, myofibril misalignment, fibrotic change, and glycolytic activation, matured MYBPC3 G115 ^∗ ECTs displayed limited phenotypes, which were primarily observed only under our new maturation protocol (i.e., hypertrophy). Altogether, ERRγ activation combined with mechanical stimulation enhanced ECT maturation, leading to a more accurate manifestation of HCM phenotypes, including non-cardiomyocyte activation, consistent with clinical observations.
Competing Interests: Declaration of interests Y.Y. and S.F. are scientific advisors of Orizuru Therapeutics, Inc. Y.Y. received research funding from Takeda Pharmaceutical Company, Ltd., and Altos Labs, Inc. Y.Y. owns stock in iPS Portal, Inc. K.D., A.S., S.I., and K.I. are employees of Takeda Pharmaceutical Company, Ltd. T.N. is an employee of Orizuru Therapeutics, Inc. T.S. is an employee of GenAhead Bio, Inc. K.M. and Y.Y. are the inventors of the patent application (WO2019/189554).
(Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)