New study enables researchers to more efficiently form human heart cells from stem cells

Lab-grown human heart cells provide a powerful tool to understand and potentially treat heart disease. However, the methods for producing human heart cells from pluripotent stem cells are not optimal. Fortunately, there is a new study from the University of Wisconsin-Madison Center for Stem Cell and Regenerative Medicine provides important insight that will help researchers grow heart cells from stem cells.

The study, recently published in eLife investigates the role of extracellular matrix (ECM) proteins in the generation of cardiac cells derived from human pluripotent stem cells (hPSCs). The ECM fills the space between cells, provides structural support and regulates the formation of tissues and organs. With a better understanding of ECM and its impact on heart development, researchers will be able to more effectively develop heart muscle cells called cardiomyocytes, which may be useful for heart repair, regeneration and cell therapy.

“How the ECM affects the generation of hPSC cardiomyocytes has been largely overlooked,” said Jianhua Zhang, senior scientist at the Stem Cell and Regenerative Medicine Center. “The better we understand how the soluble factors and the ECM proteins work in cell culture and differentiation, the closer we get to our goals.”

Researchers such as Zhang have attempted to improve the differentiation of hPSCs into cardiomyocytes, or the ability to take hPSCs, which can renew themselves indefinitely in culture, while retaining the ability to become almost any cell type in the human body and produce them in heart muscle cells to change. To investigate the role of the ECM in promoting this cardiac differentiation of hPSCs, Zhang tested a variety of proteins to see how they affected the growth and differentiation of stem cells, especially ECM proteins, including laminin-111, laminin- 521, fibronectin and collagen.

“Our study showed that ECM proteins play an important role in hPSC adhesion, growth and cardiac differentiation. And fibronectin plays an essential role and is indispensable in hPSC cardiac differentiation,” says Zhang. “By understanding the roles of ECM , this study will help to develop more robust methods and protocols for generating hPSC-CMs. In addition, this study helps not only in the field of cardiac differentiation, but also for other lineage differentiation.”

While the new study provides important insight into the development of heart cells, it builds on it a 2012 study Zhang who looked at the most efficient way to develop cardiac differentiation of stem cells.

“This study is actually a follow-up to the Matrix Sandwich method we developed for efficient cardiac differentiation of hPSCs,” Zhang says. “To grow the stem cells, we needed to have an ECM layer on the bottom of the plate. Otherwise, the stem cells would not adhere to the plate. We would then add another layer of ECM on top of the growing stem cells, and we found that this helped promote the most effective differentiation.”

While it was clear that this layering or sandwiching method differentiated hPSC cardiomyocytes more efficiently and reproducibly, researchers did not fully understand why. The new study explains why the ECM layers are crucial and identifies fibronectin as an important ECM protein in hPSC cardiomyocyte development.

“The most exciting part of this research is that I now understand why the Matrix Sandwich method worked. We were able to identify the fibronectin and its integrin receptors, as well as the downstream signaling pathways in this study,” explains Zhang. “With a better understanding of the role of ECM in stem cell growth and cardiac differentiation, we now hope to understand the role of fibronectin and other To investigate ECM proteins in advancing the hPSC cardiomyocyte transplantation for cell therapy.”

The next step could help researchers realize the full potential of using hPSC cardiomyocytes for disease modeling, drug screening, cardiac regeneration and cell therapy. This makes a lot of sense for Zhang, who started working in cardiovascular research more than 16 years ago.

“I became interested in stem cell and heart research when I started working with the stem cells and watched them turn into heart cells in a cell culture dish under a microscope,” says Zhang. “It’s been amazing. I’m more and more committed to this research and I really see the potential of using stem cell technologies to cure disease and improve our health.”

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