New Molecular Inhibitor Stimulates Tissue Regeneration

The ability to create agents that promote tissue regeneration would have overwhelmingly beneficial implications within the clinical setting. Now, a collaboration of researchers from UT Southwestern Medical Center, Case Western Reserve University, and the University of Kentucky has identified an enzyme they say regulates tissue regeneration. The scientists believe that the inhibition of this enzyme could accelerate tissue recovery from injury, disease, or even various surgical procedures in multiple organ systems.

Investigators found that by blocking the enzyme 15-hydroxy prostaglandin dehydrogenase (15-PGDH) in mice with a new compound called SW033291, they could rescue damaged bone marrow, liver, and colon tissue.    

“Patients undergoing bone marrow transplants and patients with colitis may benefit from this approach,” stated co-author James Willson, M.D., associate dean of oncology programs at UT Southwestern Medical Center and co-author on the current study. “We propose that SW033291 will be useful in accelerating recovery of bone marrow cells following a bone marrow transplant and may also be a treatment for colitis.”

The findings from this study were published recently in Science through an article entitled “Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration.”

15-PDGH is a key enzyme responsible for the biological inactivation of a group of signaling molecules, called eicosanoids, which are formed from the oxidation of long-chain fatty acid molecules. A subclass within the eicosanoids, prostaglandins are physiologically active lipid compounds that have diverse hormone-like effects in humans.

The new SW033291 molecule works by targeting a 15-PGDH-regulated pathway of bone marrow regeneration in which increased bone marrow prostaglandin drives the production of hematopoietic cytokines by CD45-positive marrow cells.  

“These inhibitors increase prostaglandin levels in a variety of tissues. For this reason, they appear to help the healing process in at least the intestines, liver, and bone marrow. We are hopeful that inhibiting 15-PGDH represents a general strategy to promote tissue repair,” explained co-author Dr. Joseph Ready, Ph.D., professor of biochemistry and member of the Simmons Cancer Center at UT Southwestern Medical Center.

The researchers first generated a strain of mice in which they genetically deleted 15-PGDH to better understand the role the enzyme played in regulating tissue levels of prostaglandins and tissue repair activity within multiple organ systems. After the development of the SW033291 compound, the collaborators wanted to investigate the therapeutic potential of 15-PGDH inhibitors in tissue regeneration.

Interestingly the researchers found that in comparison to wild-type mice, the 15-PGDH deficient mice were observed to have a twofold increase in prostaglandin levels across multiple tissues and that there was increased fitness of these tissues in response to damage. Additionally, the researchers noted that not only did the SW033291 treated mice recapitulate the phenotype of the 15-PGDH knockout mice, the drug-treated mice showed a six-day-faster reconstitution of hematopoiesis after bone marrow transplantation.

“Studying mouse models, we have shown that 15-PGDH negatively regulates tissue regeneration and repair in the bone marrow, colon, and liver,” the scientists concluded. “Of most direct utility, our observations identify 15-PGDH as a therapeutic target and provide a chemical formulation, SW033291, that is an active 15-PGDH inhibitor in vivo and that potentiates repair in multiple tissues. SW033291 or related compounds may merit clinical investigation as a strategy to accelerate recovery after bone marrow transplantation and other tissue injuries.”