Perpendicular Shear Stresses Drive Transmural Helical Remodeling in Engineered Human Ventricular Models

Tissue engineering with human induced pluripotent stem cell-derived cardiomyocytes enables unique opportunities for creating physiological models of the heart in vitro. However, there are few approaches available that can recapitulate the complex structure-function relationships that govern cardiac function at the macroscopic organ level. Here, we report a down-scaled, conical human 3D ventricular model with controllable cellular organization using multilayered, patterned cardiac sheets. Tissue engineered ventricles whose cardiomyocytes were pre-aligned parallel or perpendicular to the long axis outperformed those whose cardiomyocytes were angled or randomly oriented. Notably, the inner layers of perpendicular cardiac sheets realigned over 4 days into a parallel orientation, creating a helical transmural architecture, whereas minimal remodeling occurred in the parallel or angled sheets. Finite element analysis of engineered ventricles demonstrated that circumferential alignment leads to maximal perpendicular shear stress at the inner layer, whereas longitudinal orientation leads to maximal parallel stress. We hypothesize that cellular remodeling occurs to reduce perpendicular shear stresses in myocardium. This advanced platform provides evidence that physical forces such as shear stress drive self-organization of cardiac architecture. ### Competing Interest Statement N.P.W. is an employee of and equity holder in Sana Biotechnology. D-H.K. is a scientific founder and equity holder of Curi Bio Inc. A.S.T.S. is a scientific advisor and equity holder to Curi Bio. J.H.T. is an employee and equity holder of Tenaya Therapeutics. J.R.F. is an employee of Curi Bio. C.E.M is an employee of and equity holder in Sana Biotechnology. N.J.S. and D.L.M. are scientific advisors and equity holders of Curi Bio. N.J.S. is a co-founder and equity holder of Stasys Medical Corporation.