Homaira Hamidzada

Conference 2023 Live Talk

Talk title

Human macrophages enhance the function of bioengineered human cardiac microtissues

Authors and Affiliations

Homaira Hamidzada1-3, Simon Pascual Gil de Gomez2,3, Michael A. Laflamme,1,2,3 Gordon Keller2, Milica Radisic2 & Slava Epelman1-4

1. Department of Immunology, University of Toronto, Toronto, Canada
2. Toronto General Research Institute, University Health Network, Toronto, Canada
3. Ted Rogers Centre for Heart Research, Toronto, Canada
4. Peter Munk Cardiac Centre, Toronto, Canada

Abstract

Background

Cardiovascular disease remains the leading cause of mortality worldwide. Unlike adults, neonatal mammals possess a remarkable regenerative capacity following cardiac injury. Interestingly, primitive embryonic-derived cardiac macrophages (MFs) are absolutely required for this regeneration. In adults, primitive MFs are indispensable for both homeostatic and reparative functions in ischemic and non-ischemic cardiac injury. Current approaches for tissue engineering have largely focused on cardiomyocyte and stromal populations, overlooking the interplay of key immune subsets. We asked whether the addition of primitive MFs within human cardiac bioengineered tissues can reveal important roles in human cardiac function.

Methods

We used the Biowire II platform, a human heart-on-chip comprised of cardiomyocytes and fibroblasts. The Biowire is synthesized using iPSC or hESC-derived cardiomyocytes and human primary cardiac fibroblasts suspended in a collagen-Matrigel hydrogel matrix (Figure 1C). The tissue grows in suspension attached to two parallel, elastic POMaC wires enabling non-invasive measurement of the force generated by cardiac tissues upon systolic contraction (wire-bend). We seeded Biowires with or without human embryonic stem cell (hESC)-macrophages.

Results

Inclusion of human embryonic stem cell (hESC)-derived primitive MFs improved tissue formation within the Biowire II heart-on-a-chip platform and increased spontaneous beating rate. Importantly, MFs were functionally active and enhanced the active force generated by microtissues comprising either iPSC- or hESC-derived cardiomyocytes. In line, MF inclusion resulted in increased contraction and relaxation velocities, and improved calcium handling. Furthermore, MFs improved electrophysiological properties, with a reduced excitation threshold and increased maximum capture rate. Single-nuclei RNA sequencing revealed that cardiomyocytes adopted numerous states, with a preferential increase in proliferating and mature populations in tissues containing MFs. Reciprocally, the Biowire microenvironment promoted a cardiac-specific transcriptional identity in hESC-MFs.

Conclusions

Thus, we have developed a human heart-on-a-chip incorporating primitive cardiac MFs, highlighting for the first time their critical role in human cardiac function and a more translatable model to investigate human cardiac disease.