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Photo by Chad McNeeley
A small molecule may be able to accelerate cell recovery in bone marrow transplant (BMT) recipients and patients with liver or colon disease, researchers believe.
The molecule, SW033291, inhibits 15-PGDH, a prostaglandin-degrading enzyme that regulates tissue regeneration in multiple organs.
SW033291 accelerated hematopoietic recovery in mice that received BMTs and promoted tissue regeneration in mice with liver or colon injuries.
“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,” said James Willson, MD, of the University of Texas Southwestern Medical Center in Dallas.
He and his colleagues described their work with SW033291 in Science.
To examine the effects of inhibiting 15-PGDH on the bone marrow, the researchers conducted experiments with 15-PGDH-knockout mice and SW033291-treated mice, comparing them to control mice.
The team saw a 43% increase in neutrophil counts and a 39% increase in bone marrow Sca-1+ C-kit+ Lin– (SKL) cells in 15-PGDH knockout compared to wild-type mice. There were no significant differences in counts of other peripheral blood cells, bone marrow cellularity, or counts of bone marrow Sca-1+ C-kit+ Lin– CD48– CD150+ (SLAM) cells.
SW033291-treated mice had double the peripheral neutrophil counts of controls, a 65% increase in marrow SKL cells, and a 71% increase in marrow SLAM cells.
Results of additional experiments indicated that SW033291 works by increasing PGE2 levels in the bone marrow, and PGE2 functions through the EP2 and EP4 receptors to induce expression of CXCL12 and SCF.
The researchers also tested whether SW033291 could increase the bone marrow’s ability to attract and support new hematopoietic stem cells after BMT in mice. They found that BMT recipients treated with SW033291 had a 2- to 3-fold increase in the number of donor cells that homed to their bone marrow, compared to vehicle-treated BMT recipients.
The researchers said this SW033291-induced homing of transplanted bone marrow cells was driven, at least in part, by the induction of CXCL12 expression in CD45– nonmyeloid cells that were already resident in the bone marrow of recipient mice.
These results suggest 15-PGDH inhibition causes an increase in bone marrow PGE2, which induces the expression of bone marrow CXCL12 and SCF, and these cytokines alter the bone marrow microenvironment to better support the homing of transplanted cells.
The researchers also evaluated whether 15-PGDH inhibition promotes hematopoietic recovery after BMT. They studied lethally irradiated mice that received 200,000 strain-matched donor bone marrow cells, which were insufficient to reconstitute hematopoiesis in the mice.
When the mice were treated with SW033291, they survived for more than 30 days. All control mice, on the other hand, died between days 6 and 14.
For the last of their BMT experiments, the researchers examined the effect of SW033291 on mice transplanted with 500,000 bone marrow cells.
All SW033291-treated mice and 63% of control mice survived for 30 days, which allowed the team to compare hematopoietic recovery between the two groups. They found that SW033291 significantly accelerated the recovery of neutrophils, platelets, and red blood cells.
Experiments in mice with liver or colon injuries suggested that SW033291 can aid recovery in these models as well. 
Photo by Chad McNeeley
A small molecule may be able to accelerate cell recovery in bone marrow transplant (BMT) recipients and patients with liver or colon disease, researchers believe.
The molecule, SW033291, inhibits 15-PGDH, a prostaglandin-degrading enzyme that regulates tissue regeneration in multiple organs.
SW033291 accelerated hematopoietic recovery in mice that received BMTs and promoted tissue regeneration in mice with liver or colon injuries.
“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,” said James Willson, MD, of the University of Texas Southwestern Medical Center in Dallas.
He and his colleagues described their work with SW033291 in Science.
To examine the effects of inhibiting 15-PGDH on the bone marrow, the researchers conducted experiments with 15-PGDH-knockout mice and SW033291-treated mice, comparing them to control mice.
The team saw a 43% increase in neutrophil counts and a 39% increase in bone marrow Sca-1+ C-kit+ Lin– (SKL) cells in 15-PGDH knockout compared to wild-type mice. There were no significant differences in counts of other peripheral blood cells, bone marrow cellularity, or counts of bone marrow Sca-1+ C-kit+ Lin– CD48– CD150+ (SLAM) cells.
SW033291-treated mice had double the peripheral neutrophil counts of controls, a 65% increase in marrow SKL cells, and a 71% increase in marrow SLAM cells.
Results of additional experiments indicated that SW033291 works by increasing PGE2 levels in the bone marrow, and PGE2 functions through the EP2 and EP4 receptors to induce expression of CXCL12 and SCF.
The researchers also tested whether SW033291 could increase the bone marrow’s ability to attract and support new hematopoietic stem cells after BMT in mice. They found that BMT recipients treated with SW033291 had a 2- to 3-fold increase in the number of donor cells that homed to their bone marrow, compared to vehicle-treated BMT recipients.
The researchers said this SW033291-induced homing of transplanted bone marrow cells was driven, at least in part, by the induction of CXCL12 expression in CD45– nonmyeloid cells that were already resident in the bone marrow of recipient mice.
These results suggest 15-PGDH inhibition causes an increase in bone marrow PGE2, which induces the expression of bone marrow CXCL12 and SCF, and these cytokines alter the bone marrow microenvironment to better support the homing of transplanted cells.
The researchers also evaluated whether 15-PGDH inhibition promotes hematopoietic recovery after BMT. They studied lethally irradiated mice that received 200,000 strain-matched donor bone marrow cells, which were insufficient to reconstitute hematopoiesis in the mice.
When the mice were treated with SW033291, they survived for more than 30 days. All control mice, on the other hand, died between days 6 and 14.
For the last of their BMT experiments, the researchers examined the effect of SW033291 on mice transplanted with 500,000 bone marrow cells.
All SW033291-treated mice and 63% of control mice survived for 30 days, which allowed the team to compare hematopoietic recovery between the two groups. They found that SW033291 significantly accelerated the recovery of neutrophils, platelets, and red blood cells.
Experiments in mice with liver or colon injuries suggested that SW033291 can aid recovery in these models as well.
Photo by Chad McNeeley
A small molecule may be able to accelerate cell recovery in bone marrow transplant (BMT) recipients and patients with liver or colon disease, researchers believe.
The molecule, SW033291, inhibits 15-PGDH, a prostaglandin-degrading enzyme that regulates tissue regeneration in multiple organs.
SW033291 accelerated hematopoietic recovery in mice that received BMTs and promoted tissue regeneration in mice with liver or colon injuries.
“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,” said James Willson, MD, of the University of Texas Southwestern Medical Center in Dallas.
He and his colleagues described their work with SW033291 in Science.
To examine the effects of inhibiting 15-PGDH on the bone marrow, the researchers conducted experiments with 15-PGDH-knockout mice and SW033291-treated mice, comparing them to control mice.
The team saw a 43% increase in neutrophil counts and a 39% increase in bone marrow Sca-1+ C-kit+ Lin– (SKL) cells in 15-PGDH knockout compared to wild-type mice. There were no significant differences in counts of other peripheral blood cells, bone marrow cellularity, or counts of bone marrow Sca-1+ C-kit+ Lin– CD48– CD150+ (SLAM) cells.
SW033291-treated mice had double the peripheral neutrophil counts of controls, a 65% increase in marrow SKL cells, and a 71% increase in marrow SLAM cells.
Results of additional experiments indicated that SW033291 works by increasing PGE2 levels in the bone marrow, and PGE2 functions through the EP2 and EP4 receptors to induce expression of CXCL12 and SCF.
The researchers also tested whether SW033291 could increase the bone marrow’s ability to attract and support new hematopoietic stem cells after BMT in mice. They found that BMT recipients treated with SW033291 had a 2- to 3-fold increase in the number of donor cells that homed to their bone marrow, compared to vehicle-treated BMT recipients.
The researchers said this SW033291-induced homing of transplanted bone marrow cells was driven, at least in part, by the induction of CXCL12 expression in CD45– nonmyeloid cells that were already resident in the bone marrow of recipient mice.
These results suggest 15-PGDH inhibition causes an increase in bone marrow PGE2, which induces the expression of bone marrow CXCL12 and SCF, and these cytokines alter the bone marrow microenvironment to better support the homing of transplanted cells.
The researchers also evaluated whether 15-PGDH inhibition promotes hematopoietic recovery after BMT. They studied lethally irradiated mice that received 200,000 strain-matched donor bone marrow cells, which were insufficient to reconstitute hematopoiesis in the mice.
When the mice were treated with SW033291, they survived for more than 30 days. All control mice, on the other hand, died between days 6 and 14.
For the last of their BMT experiments, the researchers examined the effect of SW033291 on mice transplanted with 500,000 bone marrow cells.
All SW033291-treated mice and 63% of control mice survived for 30 days, which allowed the team to compare hematopoietic recovery between the two groups. They found that SW033291 significantly accelerated the recovery of neutrophils, platelets, and red blood cells.
Experiments in mice with liver or colon injuries suggested that SW033291 can aid recovery in these models as well.