Nuclear Deformation Research Could Advance Artificial Tissue Engineering | Biomedical genius

Professor Corey Neu and PhD student Benjamin Seelbinder.
Header Image: Fabrics with various structural and mechanical characteristics.

Biomedical engineering professor Corey Neu and Benjamin Seelbinder (PhDMech’19) wanted to answer two fundamental questions. How do cells adapt to their environment and how does a mechanical environment influence a cell?

What they discovered during their more than six years of research has the potential to tackle major barriers to health and advance artificial tissue engineering.

Their research, published on 2 December in Nature Biomedical Engineering and titled “Nuclear Deformation Guides Chromatin Reorganization in Cardiac Development and Disease”, found that mechanical forces guide the development of a cell through the reorganization of its nucleus and could influence future pathologies.

“We were interested in the development of healthy cells, and the health of a cell requires the nucleus to sense mechanical forces in a particular way,” Neu said.

One of those forces is tension, explained Neu and Seelbinder. The tension stretches the cell in a defined way, causing the nucleus to reorganize. This change changes gene expression, which could indicate certain diseases in patients.

This understanding of the process of cell development also helped Neu and Seelbinder conclude that scientists themselves can influence a cell. Researchers can change the environment by manipulating the voltage moving through a cell, which could be used to create more authentic artificial tissues.

Discovery

Mouse embryo
Left: Mouse embryo. Environment: Close-up on the embryonic heart. Law: Close-up of the nucleus of the embryonic cardiomyocyte.

Seelbinder, who is now a postdoctoral associate at Max Planck Institute for Molecular Cell Biology and Genetics, first discovered that mechanical forces shape nuclei by studying the cardiovascular cells of embryonic mice.

“The nucleus was a very interesting thing to study when examining the integration of force in cells, because it is large, contains all the genetic information, and has mechanical connections with all parts of the cell,” Seelbinder said. “We just started exploring and found that there is a clear pattern that should be investigated more closely.”

Seelbinder used heart cells because they contract on their own, making them the perfect model for studying nuclear deformation. Cells are known to be very sensitive to their mechanical environment.

Seelbinder noticed that the contractions made the core stiff, stiff and dense in some areas, he and Neu explained. In other regions, the nucleus appeared to be loosely organized.

“There is a certain well-defined structure that the nucleus takes; it’s not just a soft gel, ”Neu said. “There are also definite forces that occur because all of a sudden the heart cells contract during development. The mechanics are fascinating – forces don’t just occur, they are transferred to cellular substructures. “

Neu and Seelbinder concluded that contractions are the result of mechanical forces and tension moving through cells. These contractions reorganize the chromatin in each cell, which is a structural building block of the nucleus.

Cell image
Embryonic cardiomyocytes which contract show a change in nuclear organization, unlike cardiomyocytes on rigid substrates.

Neu said the discovery launched a major collaborative effort centered on the College of Engineering and Applied Science. With the help of researchers from the Paul M. Rady Department of Mechanical Engineering at the University of Colorado, Department of Molecular, Cellular, and Developmental Biology, the University of Pennsylvania and Purdue University, they confirmed that the same patterns occur in humans.

Impacts on human health

Understanding how the chromatin in a nucleus is organized is a fundamental area. The location of genes in the nucleus is important for their expression and has key implications.

Neu and Seelbinder also found that animals that underwent nuclear reorganization later in life developed pathology with symptoms that an older human with cardiovascular disease or high blood pressure might experience.

By examining adult mice with induced hypertrophy, they observed that gene expression established during development reorganized itself again in the adult stage. This leads to the loss of cell identity and cell activity. In the case of heart cells, the contractions have stopped, resulting in cardiac arrest.

“It’s not just about development, but the role of the mechanics and organization of the nucleus is also very important in later stages of life,” Neu said. “When someone develops heart disease, for example. “

Human heart
Mountain peak: Human heart samples from patients without heart failure (NHF).
Low: Human heart samples from patients with non-ischemic cardiomyopathy (NICM).

The researchers studied patients with heart conditions like cardiomyopathy, a disease that makes it harder for the heart to pump blood. Seelbinder explained that the condition suited their job well because cardiomyopathy alters the mechanical environment of the heart.

Cardiomyopathy thickens the heart muscle, causing fewer contractions and fewer nuclear deformities. Chromatin reorganizes and cell identity declines.

“If you use markers like how much blood the heart is pumping and correlate it with the reorganization of the nucleus, that was very predictive,” Seelbinder said. “This means that you can take some tissue, look at the organization of the nucleus, and find out whether that organ is functioning well or not.”

Seelbinder and Neu said these findings have become one of the most impressive things they’ve come across. This opened the door not only to diagnostic potentials, but also to therapeutic possibilities.

Artificial Tissue Engineering

Neu and Seelbinder’s research could help change the landscape of artificial tissue engineering. Their work fills gaps in the understanding of the relationship between mechanical forces and cell development in regenerative medicine.

Neu said that if researchers knew how the heart develops – which triggers the transition from a collection of cells to a fully functioning organ or organism – it is possible to mimic developmental processes.

Their research is a model of the development path, which could also pave the way for new regenerative technologies and the possibility of organ-on-chip models used in drug discovery.

“Pharmaceutical companies may want to screen for new types of drugs, for example,” Neu said. “If you have replicated heart tissue with the correct nuclei and function, if you can create a miniaturized model of a person, then it may be possible to screen for drug candidates that might be most effective in humans.”


The article by Neu and Seelbinder titled “Nuclear Deformation Guides Chromatin Reorganization in Cardiac Development and Disease” is published in Nature Biomedical Engineering, available to read here.

CU Boulder’s Department of Mechanical Engineering co-authors include a former postdoctoral researcher Soham Gosh – who is now a faculty member at Colorado State University – doctoral students Stephanie Schneider and Adrienne Scott, and Professor Sarah Calve.

Postdoctoral Fellow in Molecular, Cellular and Developmental Biology Eduard Casas, PhD candidate Alison Swearingen and Professor Justin Brumbaugh also co-authored the article.


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