Duke Researchers Find an Important Switch that Controls Organ Injury Responses

Monday, August 20, 2018
By Lindsay Key

 

Donald Fox, PhD and Erez Cohen, PhD candidate in the Fox LabDonald Fox, PhD and Erez Cohen, PhD candidate in the Fox Lab

Just like people in crisis, not every organ responds the same way when faced with an injury.

Many organs make new cells through cell division to replace those that died.  Historically, in regenerative medicine, this is seen as the best option for repairing tissue, as it restores the pre-injury appearance of the organ.

Other organs, however, —often the heart, liver, and kidney— go about it a different way.  They make the remaining cells bigger to fill the space lost to injury, a process called hypertrophy.  The new organ may or may not look like it did pre-injury.  For more than a century, scientists have sought to understand why some organs undergo hypertrophy, and if that process has any advantages over cell division.

A Duke research team led by Donald Fox, PhD, assistant professor of pharmacology and cancer biology in the School of Medicine, was able to pinpoint a gene, known as “fizzy related” that serves as an important regulator of hypertrophy.  The study was published in the journal eLife on August 17.

Using new methodology developed in the lab, the team found that the expression of this gene in a segment of a fruit fly’s intestine blocks the cell division program, which switches the repair process from cell division to hypertrophy.  

Furthermore, while they saw no difference in outcome between cell division and hypertrophy after one brief injury, fly tissue that underwent many cell divisions or many rounds of hypertrophy did show an important difference.  In those experiments, cell divisions led to organ distortion and loss of permeability, where hypertrophy had no substantial effect.  This finding in the fly model is important because the same gene is found in humans, where it is known as FZR1.

“While some strategies in regenerative medicine have focused on trying to force organs to regenerate via cell division, we show that forcing this response can have adverse effects,” said Erez Cohen, a PhD student in Fox’s lab and lead author of the paper.

“Large polyploid cells, or cells that have more than two chromosome sets such as those that are produced during hypertrophy, are often viewed as maladaptive or anti-regenerative. Our study shows that hypertrophy not only can be used when cell division is not possible, but also that it actually might protect organ integrity in some cases,” said Fox.  

The team’s next step is to use the lab’s new methodology to investigate the role of hundreds of fly genes in hypertrophy, most of which have clear matches to human disease genes. Testing the roles of such a large number of genes is also much easier to do in flies than in other laboratory model organisms such as mice.  

Other co-authors on the paper include Scott R. Allen, a PhD student in the Fox lab, and Jessica K. Sawyer, a research assistant professor in Department of Pharmacology and Cancer Biology.

Research in the lab is supported by the National Institutes of Health and the School of Medicine’s Regeneration Next initiative, which provides support to Duke faculty, trainees and staff to advance education, discovery science, translational research, and development of therapies in the field of regenerative medicine.