One of the greatest challenges facing medicine today is understanding how the body regenerates tissues damaged by disease or trauma. Recent work led by a team of researchers in the laboratory of Leonard Zon, the Grousbeck professor of pediatrics at Children’s Hospital Boston and HMS, shows that molecules that interact to shape embryonic development also cooperate in tissue regeneration in adults.
In earlier work, Trista North, now an HMS assistant professor of pathology at Beth Israel Deaconess Medical Center, and Wolfram Goessling, HMS assistant professor of medicine at Brigham and Women’s Hospital, isolated the lipid compound prostaglandin E2 (PGE2) from a chemical screen for small molecules that stimulate blood stem cell production in zebrafish embryos. PGE2 had a potent regulatory effect on blood stem cells both during development and in the adult. A clue to how PGE2 exerts these effects came from clinical evidence that prostaglandin and Wnt signaling intersect in human colon cancer. Wnts are secreted proteins found in most multicellular animals that play key roles in organ development and carcinogenesis.
In a study published in the March 20 Cell, Goessling and North investigate the possibility that the PGE2 and Wnt signaling pathways work together to regulate stem cell homeostasis. Using a combination of genetic and chemical approaches in fish embryos, they showed that PGE2 modulates Wnt signaling to stimulate blood stem cell proliferation by stabilizing beta-catenin, a downstream component of the Wnt pathway. PGE2 and Wnt activity also cooperated to promote blood stem cell regeneration in adult zebrafish following irradiation-induced marrow injury.
Goessling and North then examined whether these findings extended to mammalian biology. Indeed, interaction of PGE2 with Wnt signaling regulated the total number of blood stem cells in irradiated adult mice following bone marrow transplantation. Zon and colleagues believe they have uncovered a general mechanism the body uses to respond to injury, since the PGE2 and Wnt interaction also promoted liver recovery in mice after surgical resection of the liver.
The findings have important implications for regenerative medicine. Since directly disrupting Wnt signaling is likely to wreak havoc in the body, PGE2 provides a promising approach by which one can “modulate the modulators,” said Goessling, who is following up on the liver regeneration experiments with preclinical studies in his own lab. Given its promise in accelerating blood stem cell regeneration, PGE2 was recently FDA-approved for use in clinical transplantation trials to treat leukemia. “This is the first example of taking a small molecule from a zebrafish screen and bringing it to the clinic,” said North. The team plans to investigate whether PGE2 also functions in other regenerative settings.
Students may contact Wolfram Goessling (wgoessling@partners.org), Trista North (tnorth@bidmc.harvard.edu), or Leonard Zon (zon@enders.tch.harvard.edu) for more information.
Conflict Disclosure: WG, TN, and LZ hold patents relating to the use of PGE2 and Wnt in blood stem cells and organ regeneration. LZ is a consultant and stockholder of FATE Therapeutics, which licenses this technology.
Funding Sources: The National Institutes of Health and Howard Hughes Medical Institute
