Epicardioid Organoid Heart Emulates Human Heart Development

By Emulating Heart Conditions in Organoids, Drugs Could be Tested Directly on Them

Definition

Epicardium / Cardiomyocytes

Epicardium:

The epicardium refers to the outermost protective layer of the heart. The epicardium is composed of mesothelium, a cell type that covers and protects most of the internal organs of the body as well as fat and connective tissue. The epicardium predominantly surrounds the heart and the roots of the coronary vessels emerging from it, including the aorta, the superior vena cava, and inferior vena cava.

Cardiomyocytes:

Cardiomyocytes are striated, uninucleate muscle cells found exclusively in the heart muscle. A unique cellular and physiological feature of cardiomyocytes are intercalated discs, which contain cell adhesions such as gap junctions, to facilitate cell-cell communication. From the perspective of cardiology, a cardiomyocyte is the cell responsible for the contraction of the heart by utilizing an intricate network of contractile proteins and ion transporters for this work - with the main purpose of effectively executing the contraction-relaxation cycle.

Main Digest

"Epicardioid Single-Cell Genomics Uncovers Principles of Human Epicardium Biology in Heart Development and Disease" - Nature Biotechnology.

A team at the Technical University of Munich (TUM) has induced stem cells to emulate the development of the human heart. The result is a sort of "mini-heart" known as an organoid. It will permit the study of the earliest development phase of our heart and facilitate research on diseases.

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The human heart starts forming approximately three weeks after conception. This places the early phase of heart development in a time when women are often still unaware of their pregnancy. That is one reason why we still have little knowledge of many details of how the heart is formed. Findings from animal studies are not fully transferable to humans. An organoid developed at TUM could prove helpful to researchers.

Ball of 35,000 Cells

The team working with Alessandra Moretti, Professor of Regenerative Medicine in Cardiovascular Disease, has developed a method for making a sort of "mini-heart" using pluripotent stem cells. Around 35,000 cells are spun into a sphere in a centrifuge. Over a period of several weeks, different signaling molecules are added to the cell culture under a fixed protocol.

"In this way, we mimic the signaling pathways in the body that control the developmental program for the heart," explains Alessandra Moretti. The group has now published its work in the journal Nature Biotechnology.

First Ever Epicardioids

The resulting organoids are about half a millimeter in diameter. Although they do not pump blood, they can be stimulated electrically and are capable of contracting like human heart chambers. Prof. Moretti and her team are the first researchers in the world to successfully create an organoid containing both heart muscle cells (cardiomyocytes) and cells of the outer layer of the heart wall (epicardium). In the young history of heart organoids - the first were described in 2021 - researchers had previously created only organoids with cardiomyocytes and cells from the inner layer of the heart wall (endocardium).

"To understand how the heart is formed, epicardium cells are decisive," says Dr. Anna Meier, first author of the study. "Other cell types in the heart, for example in connecting tissues and blood vessels, are formed from these cells. The epicardium also plays a very important role in forming the heart chambers." The team has appropriately named the new organoids "epicardioids".

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New Cell Type Discovered

Along with the method for producing the organoids, the team has reported its first new discoveries. Through the analysis of individual cells they have determined that precursor cells of a type only recently discovered in mice are formed around the seventh day of the development of the organoid. The epicardium is formed from these cells. "We assume that these cells also exist in the human body - if only for a few days," says Prof. Moretti.

These insights may also offer clues as to why the fetal heart can repair itself, a capability almost entirely absent in the heart of an adult human. This knowledge could help to find new treatment methods for heart attacks and other conditions.

Producing Personalized Organoids

The team also showed that the organoids can be used to investigate the illnesses of individual patients. Using pluripotent stem cells from a patient suffering from Noonan syndrome, the researchers produced organoids that emulated characteristics of the condition in a Petri dish. Over the coming months the team plans to use comparable personalized organoids to investigate other congenital heart defects.

With the possibility of emulating heart conditions in organoids, drugs could be tested directly on them in the future.

"It is conceivable that such tests could reduce the need for animal experiments when developing drugs," says Alessandra Moretti.

Organoid Research is a Key Research Area

The researchers have registered an international patent for the process of creating heart organoids. The Epicardioid model is one of several organoid projects at TUM. At the Center for Organoid Systems work groups from various departments and chairs will collaborate. They will conduct interdisciplinary research into pancreas, brain and heart organoids with state-of-the-art imaging and cellular analysis to study the formation of organs, cancer and neurodegenerative diseases and achieve progress for medicine with human 3D systems.

More information:

• In an accompanying study in Nature Communications, the signaling molecules responsible for the growth of the heart organoids were decoded further and the importance of retinoic acid for programming specific heart precursor cells in the formation of the heart were analyzed.
• The research on the organoids was funded through the ERC Advanced Grant BIOCARD (788381) of Prof. Moretti.

Publications:

A.B. Meier, D. Zawada, M. T. De Angelis, L. D. Martens, G. Santamaria, S. Zengerle, M. Nowak-Imialek, J. Kornherr, F. Zhang, Q. Tian, C. M. Wolf, C. Kupatt, M. Sahara, P. Lipp, F.J. Theis, J. Gagneur, A. Goedel, K.-L. Laugwitz, T. Dorn, A. Moretti, "Epicardioid single-cell genomics uncovers principles of human epicardium biology in heart development and disease", Nature Biotechnology (2023). DOI: 10.1038/s41587-023-01718-7.

D. Zawada, J. Kornherr, A.B. Meier, G. Santamaria, T. Dorn, M. Nowak-Imialek, D. Ortmann, F. Zhang, M. Lachmann, M. Dreßen, M. Ortiz, S.C. Harmer, M. Nobles, A. Tinker, M.T. De Angelis., R.A. Pedersen, P. Grote, K.-L. Laugwitz, A. Moretti, A. Goedel, "Retinoic acid signaling modulation guides in vitro specification of human heart field-specific progenitor pools". Nature Communications (2023). DOI:10.1038/s41467-023-36764-x.

Attribution/Source(s):

This peer reviewed article relating to our Organoids section was selected for publishing by the editors of Disabled World due to its likely interest to our disability community readers. Though the content may have been edited for style, clarity, or length, the article "Epicardioid Organoid Heart Emulates Human Heart Development" was originally written by Technical University of Munich (TUM), and published by Disabled-World.com on 2023-04-04. Should you require further information or clarification, Technical University of Munich (TUM) can be contacted at tum.de/en/. Disabled World makes no warranties or representations in connection therewith.

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