A team of engineers and biologists at the University of Colorado Boulder have discovered new insights into how mechanical forces guide the development of cells early in the life of an organism, and might lead to pathologies in the future.
The findings could one day help researchers develop new treatments for heart disease in humans and even develop more authetic artificial tissue in the lab. The group, led by biomedical engineer Corey Neu, published its results Dec. 2 in the journal Nature Biomedical Engineering.
"We were interested in the development of healthy cells, and the health of a cell requires that the nucleus senses mechanical forces in a particular way," said Neu, professor of biomedical engineering at CU Boulder.
One of those forces is tension, explained Neu and study co-author Benjamin Seelbinder, a former graduate student in mechanical engineering at CU Boulder. Tension stretches the cell in a defined way, resulting in the reorganization of its nucleus—the small structure within a cell that stores DNA. That modification changes the expression of genes, which could indicate certain diseases in patients.
The upside is that researchers could also manipulate the same tension moving through a cell, leading to new advances in medicine and beyond, the researcher said.
The discovery
Seelbinder, who is now a postdoctoral associate at the Max Planck Institute of Molecular Cell Biology and Genetics, first discovered that mechanical forces shape nuclei while studying the cardiovascular cells of embryotic mice.
He used heart cells because they contract on their own, making them the perfect model to study nuclear deformation. Seelbinder noticed the contractions caused the nucleus to be stiff, rigid and dense in certain areas. In other areas, the nucleus appeared to be loosely organized.
"There is a certain well-defined structure that the nucleus takes on," Neu said. "It is not just a soft gel."
Neu and Seelbinder concluded the contractions result from mechanical forces and tension moving through cells. Those contractions reorganize each cell's chromatin, a mixture of proteins, DNA and other molecules within a nucleus that holds an organism's genetic code.
Human health
Those mechanics also matter as organisms age. Neu and Seelbinder found, for example, animals that experienced nuclear reorganization later in life developed pathology with symptoms that an older human with cardiovascular disease or hypertension might experience. In some cases, the gene expression established during development reorganized again when mice became adults. That lead to the loss of cell identity and cell activity. Contractions in heart cells stopped, leading to cardiac arrest.
"It is not just about the development, but the role of the mechanics and the organization of the nucleus is also really important at later stages of life," Neu said.
To build on those findings, the researchers studied patients with heart conditions like cardiomyopathy, a disease that makes it harder for the heart to pump blood. Cardiomyopathy thickens the heart muscle, causing fewer contractions and less nuclear deformation. As a result, the chromatin reorganizes and cellular identity declines.
"If you use markers like how much blood does the heart pump and correlate it over the reorganization of the nucleus, it was highly predictive," Seelbinder said. "That means you can take a little bit of the tissue, look at the organization of the nucleus and can tell whether that organ functions well or not."
He added that the findings opened the door not just for diagnostic potentials, but for potentially new therapies for heart disease, as well.
Artificial tissue
Neu and Seelbinder's research could also help change the landscape for artificial tissue engineering. Neu said if researchers know how the heart develops—what triggers the transition from a collection of cells to a fully functional organ or organism—they could potentially mimic that developmental processes in the lab.
Their research is a blueprint of the developmental path, which could also set the stage for new regenerative technologies and the possibility of organ-on-chip models used in drug discovery.
"Pharmaceutical companies may want to screen new kinds of drugs, for example," Neu said. "If you have a 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 candidate drugs that might be most effective in humans."
Scientists from Purdue University and the University of Pennsylvania also contributed to this research. Other CU Boulder co-authors from the Paul M. Rady Department of Mechanical Engineering included former postdoctoral researcher Soham Ghosh, PhD students Stephanie Schneider and Adrienne Scott and Professor Sarah Calve. Postdoctoral associate Eduard Casas, PhD student Alison Swearingen and Professor Justin Brumbaugh from the Department of Molecular, Cellular and Developmental Biology co-authored the paper, as well.
The research was supported in part by a CAREER grant from the National Science Foundation, and research grants from the National Institutes of Health.
