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zebrafish used in the study
Image by Jonathan Henninger
and Vera Binder
Using zebrafish drug-screening models, researchers have identified a family of lipids that aid the engraftment of hematopoietic stem and progenitor cells (HSPCs).
The lipids, known as epoxyeicosatrienoic acids (EETs), boosted HSPC engraftment in zebrafish and mice.
The researchers therefore believe EETs could help make human HSPC transplants, particularly umbilical cord blood transplants, more efficient and effective.
“Ninety percent of cord blood units can’t be used because they’re too small,” said Leonard Zon, MD, of Boston Children’s Hospital in Massachusetts.
“If you add these chemicals, you might be able to use more units. Being able to get engraftment allows you to pick a smaller cord blood sample that might be a better match.”
Dr Zon and his colleagues described their work with EETs in Nature.
EETs appear to work by stimulating cell migration. They were among the top hits in a screen of 500 known compounds the researchers conducted.
In the past, such screens have led Dr Zon’s team to compounds that boost HSPC numbers, such as prostaglandin. But the new drug screen was designed to assess HSPCs’ transplantability and engraftment.
The screen was done in a lab-created strain of zebrafish called Casper. Because Casper is translucent, Dr Zon and his colleagues could visually compare the engraftment of transplanted HSPCs chemically tagged to glow green or red.
The researchers first used tagging to color the fishes’ marrow either red or green, then removed HSPCs for transplantation. The green cells were incubated with various chemicals, while the red cells were left untreated.
The team then injected a mixture of green and red HSPCs into other groups of zebrafish (10 fish per test chemical). And they visually tracked the cells’ activity, measuring the green-to-red ratio.
“The expectation was that if a chemical didn’t increase engraftment, all the fish would be equal parts red and green,” Dr Zon said. “But if it was effective, green marrow would predominate.”
That was the case for green marrow incubated with EETs, a finding that held up over thousands of transplants.
“In a mouse system, this experiment would cost $3 million,” Dr Zon noted. “In fish, it cost about $150,000.”
In a smaller-scale set of mouse experiments, the team confirmed EETs’ efficacy in promoting homing and engraftment of HSPCs.
EETs are chemical cousins of prostaglandin. Both are made from arachidonic acid, and both are made during inflammation. But EETs work in a different way, by activating the PI3K pathway. EETs also enhanced PI3K activity in human blood vessel cells in vitro.
After more studies in human cells to determine exactly how EETs work, Dr Zon hopes to begin clinical trials of EETs within the next 2 years, likely in the setting of cord blood transplant. The lab is also investigating its other top hits from the zebrafish screen.
“Every new pathway that we find has the chance of making stem cell engraftment and migration even better,” Dr Zon said. “I think we’ll end up being able to manipulate this process.” 
zebrafish used in the study
Image by Jonathan Henninger
and Vera Binder
Using zebrafish drug-screening models, researchers have identified a family of lipids that aid the engraftment of hematopoietic stem and progenitor cells (HSPCs).
The lipids, known as epoxyeicosatrienoic acids (EETs), boosted HSPC engraftment in zebrafish and mice.
The researchers therefore believe EETs could help make human HSPC transplants, particularly umbilical cord blood transplants, more efficient and effective.
“Ninety percent of cord blood units can’t be used because they’re too small,” said Leonard Zon, MD, of Boston Children’s Hospital in Massachusetts.
“If you add these chemicals, you might be able to use more units. Being able to get engraftment allows you to pick a smaller cord blood sample that might be a better match.”
Dr Zon and his colleagues described their work with EETs in Nature.
EETs appear to work by stimulating cell migration. They were among the top hits in a screen of 500 known compounds the researchers conducted.
In the past, such screens have led Dr Zon’s team to compounds that boost HSPC numbers, such as prostaglandin. But the new drug screen was designed to assess HSPCs’ transplantability and engraftment.
The screen was done in a lab-created strain of zebrafish called Casper. Because Casper is translucent, Dr Zon and his colleagues could visually compare the engraftment of transplanted HSPCs chemically tagged to glow green or red.
The researchers first used tagging to color the fishes’ marrow either red or green, then removed HSPCs for transplantation. The green cells were incubated with various chemicals, while the red cells were left untreated.
The team then injected a mixture of green and red HSPCs into other groups of zebrafish (10 fish per test chemical). And they visually tracked the cells’ activity, measuring the green-to-red ratio.
“The expectation was that if a chemical didn’t increase engraftment, all the fish would be equal parts red and green,” Dr Zon said. “But if it was effective, green marrow would predominate.”
That was the case for green marrow incubated with EETs, a finding that held up over thousands of transplants.
“In a mouse system, this experiment would cost $3 million,” Dr Zon noted. “In fish, it cost about $150,000.”
In a smaller-scale set of mouse experiments, the team confirmed EETs’ efficacy in promoting homing and engraftment of HSPCs.
EETs are chemical cousins of prostaglandin. Both are made from arachidonic acid, and both are made during inflammation. But EETs work in a different way, by activating the PI3K pathway. EETs also enhanced PI3K activity in human blood vessel cells in vitro.
After more studies in human cells to determine exactly how EETs work, Dr Zon hopes to begin clinical trials of EETs within the next 2 years, likely in the setting of cord blood transplant. The lab is also investigating its other top hits from the zebrafish screen.
“Every new pathway that we find has the chance of making stem cell engraftment and migration even better,” Dr Zon said. “I think we’ll end up being able to manipulate this process.”
zebrafish used in the study
Image by Jonathan Henninger
and Vera Binder
Using zebrafish drug-screening models, researchers have identified a family of lipids that aid the engraftment of hematopoietic stem and progenitor cells (HSPCs).
The lipids, known as epoxyeicosatrienoic acids (EETs), boosted HSPC engraftment in zebrafish and mice.
The researchers therefore believe EETs could help make human HSPC transplants, particularly umbilical cord blood transplants, more efficient and effective.
“Ninety percent of cord blood units can’t be used because they’re too small,” said Leonard Zon, MD, of Boston Children’s Hospital in Massachusetts.
“If you add these chemicals, you might be able to use more units. Being able to get engraftment allows you to pick a smaller cord blood sample that might be a better match.”
Dr Zon and his colleagues described their work with EETs in Nature.
EETs appear to work by stimulating cell migration. They were among the top hits in a screen of 500 known compounds the researchers conducted.
In the past, such screens have led Dr Zon’s team to compounds that boost HSPC numbers, such as prostaglandin. But the new drug screen was designed to assess HSPCs’ transplantability and engraftment.
The screen was done in a lab-created strain of zebrafish called Casper. Because Casper is translucent, Dr Zon and his colleagues could visually compare the engraftment of transplanted HSPCs chemically tagged to glow green or red.
The researchers first used tagging to color the fishes’ marrow either red or green, then removed HSPCs for transplantation. The green cells were incubated with various chemicals, while the red cells were left untreated.
The team then injected a mixture of green and red HSPCs into other groups of zebrafish (10 fish per test chemical). And they visually tracked the cells’ activity, measuring the green-to-red ratio.
“The expectation was that if a chemical didn’t increase engraftment, all the fish would be equal parts red and green,” Dr Zon said. “But if it was effective, green marrow would predominate.”
That was the case for green marrow incubated with EETs, a finding that held up over thousands of transplants.
“In a mouse system, this experiment would cost $3 million,” Dr Zon noted. “In fish, it cost about $150,000.”
In a smaller-scale set of mouse experiments, the team confirmed EETs’ efficacy in promoting homing and engraftment of HSPCs.
EETs are chemical cousins of prostaglandin. Both are made from arachidonic acid, and both are made during inflammation. But EETs work in a different way, by activating the PI3K pathway. EETs also enhanced PI3K activity in human blood vessel cells in vitro.
After more studies in human cells to determine exactly how EETs work, Dr Zon hopes to begin clinical trials of EETs within the next 2 years, likely in the setting of cord blood transplant. The lab is also investigating its other top hits from the zebrafish screen.
“Every new pathway that we find has the chance of making stem cell engraftment and migration even better,” Dr Zon said. “I think we’ll end up being able to manipulate this process.”