Immunoengineering the Human Heart

Reposted from UHN Research Communications.

A new study from Toronto General Hospital Research Institute (TGHRI) and McEwen Stem Cell Institute (McEwen) has uncovered a novel method to model the involvement of yolk sac macrophages—precursors to immune cells during embryonic development—in human heart development.

Cardiac macrophages—immune cells within the heart’s muscular tissue—originate from the yolk sac and migrate to the heart during early embryonic development. These primitive macrophages remain in the adult heart and are primarily maintained through self-renewal independent of white blood cells such as monocytes.

“The role of macrophages during cardiac development is poorly understood,” says Dr. Slava Epelman, Senior Scientist at TGHRI and co-senior author of the study. “There is evidence suggesting that these macrophages are involved in artery development and the growth of lymphatic vessels, which transport lymph throughout your body. However, this evidence is based on experimental models, not human tissue, and beyond these roles, virtually nothing is known.”

A major barrier to studying macrophages during development is the lack of access to developing human cardiac tissue. Recently, tissue models of the human heart, such as organoids—3D cellular clusters—and other engineered tissues using human pluripotent stem cells (hPSCs)—cells in the body that have the potential to become any type of cell—have been developed. However, these models have not yet been made to include macrophages.

The research team, including co-senior authors Dr. Milica Radisic, Senior Scientist at TGHRI, Dr. Gordon Keller, Director of McEwen, and Dr. Michael Laflamme, Senior Scientist at McEwen, collaborated to address this gap in the field. The team aimed to engineer primitive macrophages from stem cells to better understand cardiac macrophages, their interactions with other cardiac tissue, and their role in development and tissue function.

“Using a previously established system, we generated 3D contractile cardiac tissue composed of stem cell-derived cardiomyocytes and fibroblasts that stably integrate with stem cell-derived macrophages (hESC-macrophages),” says Homaira Hamidzada, a doctoral candidate in Dr. Epelman’s lab and first author of the study.

“We demonstrated that these hESC-macrophages enhance the electromechanical properties of developing cardiac tissue— such as the contraction and relaxation of muscle tissue— and promote heart muscle maturation.”

The team also discovered that these stem cell-derived macrophages clear out dying heart cells through a process dependent on a molecule called phosphatidylserine. This action reduces stress and cell death of cardiomyocytes, and promotes the development of a tissue that more closely resembles human fetal cardiac development, as indicated by tests of gene activity and metabolism.

This study provides the first description of cardiac macrophages during early human heart development, showing that hESC-macrophages play a crucial role in heart tissue development and function.

Furthermore, integrating macrophages into engineered human cardiac tissue leads to an improved model for human heart development, enabling more detailed studies using engineered cardiac tissue that closely replicates human tissue properties.

This work was supported by the Canadian Institutes of Health Research, the Ted Rogers Centre for Heart Research, the Peter Munk Cardiac Centre, Medicine by Design, the Stem Cell Network, the National Institutes of Health and UHN Foundation.

Dr. Slava Epelman is an Associate Professor in Laboratory Medicine & Pathobiology at the University of Toronto (U of T) and the Lorretta Rogers Chair in Immunobioengineering at the Ted Rogers Centre for Heart Research. Dr. Gordon Keller is a Professor in Medical Biophysics at U of T. Dr. Milica Radisic is a Tier 1 Canada Research Chair in Organ-on-a-Chip Engineering and Professor in the Institute of Biomedical Engineering and the Donnelly Centre for Cellular and Biomolecular Research at U of T. Dr. Michael Laflamme is a Tier 1 Canada Research Chair in Cardiovascular Regenerative Medicine and a Professor in Laboratory Medicine & Pathobiology at U of T.

Co-authors Dr. Milica Radisic, Dr. Yimu Zhao, and Qinghua Wu are inventors on patents related to the Biowire II cardiac tissue cultivation and maturation protocols that are used as a main experimental system in this manuscript. Dr. Milica Radisic and Dr. Yimu Zhao receive royalty payments and annual fees for licensing of related inventions to Valo Health and receive milestone payments from Valo Health related to successful discovery and translation of molecules using the Biowire II platform.

Hamidzada, H., Pascual-Gil, S., Wu, Q. et al. Primitive macrophages induce sarcomeric maturation and functional enhancement of developing human cardiac microtissues via efferocytic pathways(link is external). Nat Cardiovasc Res 3, 567–593 (2024). https://doi.org/10.1038/s44161-024-00471-7