Photo by Chad McNeeley
HSCT preparation
New research published in The Journal of Clinical Investigation suggests the protein Del-1 regulates the hematopoietic stem cell (HSC) niche.
Researchers therefore believe that targeting Del-1 could be an effective way to improve HSC transplants (HSCTs) for donors and recipients.
There may also be ways to modulate levels of Del-1 to enhance immune cell production in patients with certain hematologic malignancies.
“Because the hematopoietic stem cell niche is so important for the creation of bone marrow and blood cells and because Del-1 is a soluble protein and is easily manipulated, one can see that it could be a target in many potential applications,” said study author George Hajishengallis, DDS, PhD, of the University of Pennsylvania School of Dental Medicine in Philadelphia.
“I think that Del-1 represents a major regulator of the hematopoietic stem cell niche,” added study author Triantafyllos Chavakis, MD, PhD, of the Technical University of Dresden in Germany. “It will be worthwhile to study its expression in the context of hematopoietic malignancy.”
This research began when Drs Hajishengallis and Chavakis identified Del-1 as a potential drug target for gum disease. They found the protein prevents inflammatory cells from moving into the gums.
Both researchers and their labs also discovered that Del-1 was expressed in the bone marrow as well. So the researchers began following up to determine the protein’s function there.
“In the beginning, I thought it would have a simple function, like regulating the exit of mature leukocytes from the marrow into the periphery, something analogous to what it was doing in the gingiva,” Dr Hajishengallis said. “But it turned out it had a much more important and global role than what I had imagined.”
The researchers’ investigations revealed that Del-1 was expressed by at least 3 cell types that support HSCs: arteriolar endothelial cells, CXCL12-abundant reticular cells, and cells of the osteoblastic lineage.
Using mice deficient in Del-1, the researchers found the protein promotes proliferation and differentiation of HSCs, sending more progenitor cells down a path toward becoming myeloid cells rather than lymphocytes.
In HSCT experiments, the team discovered the presence of Del-1 in recipient bone marrow is required for the transplanted HSCs to engraft in the recipient and to facilitate the process of myelopoiesis.
When the researchers mimicked a systemic infection in mice, animals deficient in Del-1 were slower to begin making myeloid cells again compared to mice with normal Del-1 levels.
“We saw roles for Del-1 in both steady-state and emergency conditions,” Dr Hajishengallis said.
He and his colleagues also identified the protein with which Del-1 interacts, the ß3 integrin, perhaps pointing to a target for therapeutic interventions down the line.
The researchers see potential applications in HSCTs, for both donors and recipients.
In donors, blocking the interaction between Del-1 and HSCs could enhance the mobilization of those progenitors into the bloodstream. This could be helpful for increasing donor cell numbers for transplantation.
HSCT recipients, on the other hand, may need enhanced Del-1 interaction to ensure the transplanted cells engraft and begin making new blood cells more rapidly.
In addition, people undergoing chemotherapy who develop febrile neutropenia might benefit from the role of Del-1 in supporting the production of immune-related blood cells such as neutrophils.
“It’s easy to think of practical applications for these findings,” Dr Hajishengallis said. “Now, we need to find out whether it works in practice, so our studies continue.”
