ISCRM Labs Collaborate to Grow Heart Tissue In Vitro

Heart failure is the leading cause of death in the world. In the United States alone, hundreds of thousands of people succumb to the disease every year, while the costs of care and lost productivity drain more than $200 billion from the economy.

Recent breakthroughs in stem cell research offer hope for new treatments that could help patients regrow muscle tissue after heart attacks, a key to achieving more complete recovery.

However, challenges remain.

Disruption to blood flow during a heart attack leads to significant loss of heart muscle and, subsequently, heart functioning. For that reason, restoring adequate blood flow, or perfusion, is critical. And, heart muscle grown from stem cells has to survive and integrate properly with host tissue.

One UW Medicine team, working at the intersection of tissue engineering, stem cell biology, and optical imaging, has taken these challenges on – and is making exciting progress.

The results of a recent investigation demonstrating the effectiveness of in vitro vascularization, (the formation of blood vessels) for infarcted rat heart are detailed in a new article (Patterned human microvascular grafts enable rapid vascularization and increase perfusion in infarcted rat hearts), co-authored by Dr. Ying Zheng and Dr. Charles Murry, and published by the journal Nature Communications.

Dr. Ying Zheng is an Associate Professor in the Department of Bioengineering and an ISCRM faculty member.

The study was a collaboration between the labs of Dr. Zheng and Dr. Murry, both faculty members in the Institute for Stem Cell and Regenerative Medicine (ISCRM). Dr. Zheng is an Associate Professor in the Department of Bioengineering. Dr. Murry is a Professor affiliated with the Departments of Pathology, Bioengineering, and Medicine/Cardiology.

“I come from a mechanical background,” Dr. Zheng says. “I love thinking about the dynamics of blood flow. Our whole bodies are vascularized. And this network of vessels is dynamic and interconnected, like a transportation system that remodels itself all the time.”

Dr. Zheng uses the word remodeling purposefully. She and Dr. Murry are determined to develop new ways to help the heart rebuild after a major trauma, like a heart attack. In this study, they set out to show that by growing stem cell-derived heart tissue in vitro – and by building the tissue’s blood vessels properly – they could improve integration with the heart’s blood vessels and improve tissue blood flow.

“We wanted to solve a problem that is at least 20 years old,” explains Dr. Zheng. “How can we construct a tissue patch in vitro that can promote heart regeneration inside the body?”

Dr. Charles Murry is the Conner Chair and Professor of Pathology, Bioengineering and Medicine/Cardiology, Director, Institute for Stem Cell and Regenerative Medicine, and Co-Director, Center for Cardiovascular Biology

To do that, the research team used human stem cells to create a living vascularized construct (or a patch) in the lab. The tissue, which would eventually be implanted into the hearts of rats recovering from heart attacks, was vascularized and perfused in the lab, meaning it had a functioning network of blood vessels that mimics the vasculature of an actual heart.

“Being able to organize the vessels in the tissue outside the body was very important,” explains Dr. Zheng. “When we implanted the patch, we saw that the stem cell-derived tissue integrated effectively with the host’s coronary circulation. This improved blood flow to the engineered tissue and gave it the nutrients it needed to survive.”

Observing the integration of the lab-grown tissue with the heart tissue inside the rats was the first sign of success. For quantitative evidence, Dr. Zheng and Dr. Murry enlisted the expertise of Dr. Ricky Wang, a Professor in the Department of Bioengineering.

Histology of vascularized cardiac constructs 5 days after implantation showed more cardiomyocytes retention and higher vessel density

The collaboration was crucial. Dr. Zheng and Dr. Murry wanted to measure the velocity of the blood flow inside the graft of the stem cell-derived tissue and the rat heart tissue. However, measuring blood flow in the heart is especially difficult because the vessels are embedded in dense tissue. Optical microangiography imaging techniques developed by Dr. Wang, and used for the first time in this study, revealed that blood flow within the grafts was twenty-fold higher than any existing type of graft, a strong indicator that nurturing the tissue in the lab before implantation created a healthier environment for the heart cells.

Additionally, genomic analysis was conducted by Dr. Yuliang Wang, a Research Assistant Professor in the Department of Computer Science & Engineering, and an ISCRM faculty member.

Dr. Zheng spoke to the significance of the findings. “To our knowledge, this is the first demonstration that building organized blood vessels with perfusion outside the body leads to improved integration with host blood vessels and better tissue blood flow. We expect the study to have multiple implications for the future of cardiac tissue engineering and regenerative medicine.”

Other contributing authors are Bioengineering graduate students Meredith A. Redd and Nicole Zeinstra (co-first authors) in Zheng and Murry labs; Wan Qin and Wei Wei in Wang lab; and animal surgeon Amy Martinson in Murry lab. The work is funded by National Institute of Health grants.

Citations

Meredith A. Redd, Ph.D 1-3#, Nicole Zeinstra1-3#, Wan Qin, Ph.D 1, Wei Wei 1, Amy Martinson 2-4, Yuliang Wang3,5, Ruikang K. Wang, Ph.D 1, Charles E. Murry, M.D., Ph.D.1-4,6*, Ying Zheng, Ph.D.1-3*

1Department of Bioengineering, 2Center for Cardiovascular Biology, 3Institute for Stem Cell and Regenerative Medicine, 4Department of Pathology, 5Paul G. Allen School of Computer Science & Engineering, 6Department of Medicine/Cardiology, University of Washington, Seattle, WA 98109.

# These authors contributed equally.

* Corresponding authors:

Ying Zheng, PhD., yingzy@uw.edu

Charles E. Murry, PhD., murry@uw.edu