Matrix Architecture and Mechanics Regulate Myofibril Organization, Costamere Assembly, and Contractility in Engineered Myocardial Microtissues

Samuel J DePalma; Javiera Jilberto; Austin E Stis; Darcy D Huang; Jason Lo; Christopher D Davidson; Aamilah Chowdhury; Robert N Kent 3rd; Maggie E Jewett; Hiba Kobeissi; Christopher S Chen; Emma Lejeune; Adam S Helms; David A Nordsletten; Brendon M Baker

doi:10.1002/advs.202309740

Matrix Architecture and Mechanics Regulate Myofibril Organization, Costamere Assembly, and Contractility in Engineered Myocardial Microtissues

Adv Sci (Weinh). 2024 Nov 18:e2309740. doi: 10.1002/advs.202309740. Online ahead of print.

Authors

Samuel J DePalma¹, Javiera Jilberto¹, Austin E Stis¹, Darcy D Huang¹, Jason Lo¹, Christopher D Davidson¹, Aamilah Chowdhury¹, Robert N Kent 3rd¹, Maggie E Jewett¹, Hiba Kobeissi², Christopher S Chen^{3

4}, Emma Lejeune², Adam S Helms⁵, David A Nordsletten^{1

6

7}, Brendon M Baker^{1

8}

Affiliations

¹ Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA.
² Department of Mechanical Engineering, Boston University, Boston, MA, 02215, USA.
³ Department of Biomedical Engineering, Boston University, Boston, MA, 02215, USA.
⁴ Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.
⁵ Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
⁶ Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI, 48109, USA.
⁷ Department of Biomedical Engineering, School of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, London, SE1 7EH, UK.
⁸ Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA.

PMID: 39558513
DOI: 10.1002/advs.202309740

Abstract

The mechanical function of the myocardium is defined by cardiomyocyte contractility and the biomechanics of the extracellular matrix (ECM). Understanding this relationship remains an important unmet challenge due to limitations in existing approaches for engineering myocardial tissue. Here, they established arrays of cardiac microtissues with tunable mechanics and architecture by integrating ECM-mimetic synthetic, fiber matrices, and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), enabling real-time contractility readouts, in-depth structural assessment, and tissue-specific computational modeling. They found that the stiffness and alignment of matrix fibers distinctly affect the structural development and contractile function of pure iPSC-CM tissues. Further examination into the impact of fibrous matrix stiffness enabled by computational models and quantitative immunofluorescence implicates cell-ECM interactions in myofibril assembly, myofibril maturation, and notably costamere assembly, which correlates with improved contractile function of tissues. These results highlight how iPSC-CM tissue models with controllable architecture and mechanics can elucidate mechanisms of tissue maturation and disease.

Keywords: biomaterials; cardiac tissue engineering; cardiomyocytes; electrospinning; extracellular matrix; induced pluripotent stem cells; mechanosensing.

Abstract

Grants and funding