Research Advances Understanding of Bone Marrow Transplants

Researchers have identified new functions of the angiogenin (ANG) protein that plays a significant role in the regulation of blood cell formation, a process that is critical in bone marrow transplantation and recovery from radiation-induced bone marrow failure.

In the study published in Cell, researchers were able to show for the first time that ANG simultaneously reduced proliferation of stem cells, while promoting the proliferation of myeloid progenitor cells that give rise to mature myeloid cells. These findings have significant implications for human stem cell transplantation and radiation exposure, and may lead to important therapeutic interventions of improved treatment effectiveness.

“We knew that ANG was involved in promoting cell growth so it was not unexpected to find that ANG stimulated proliferation of myeloid progenitor cells,” said senior study author Guo-fu Hu, PhD. “But it was surprising to find that ANG also suppresses growth of stem cells and that it accomplishes these divergent promotion or suppression functions through RNA processing events specific to individual cell types. Our discoveries suggest considerable therapeutic potential.”

These 2-pronged processes are accomplished by a novel molecular regulating mechanism.

For cancer patients who undergo stem cell transplantation they are met with 2 challenges: The short-term challenge of having enough white blood cells to fight any potential infections immediately after the transplant and the long-term challenge of sustaining stem cell function to maintain immunity.

Patients given large doses of radiation are faced with challenges of radiation-induced bone marrow failure.

In the study, researchers used a series of experiments that involved insolating and describing the divergent regulatory functions of AMG. They were able to demonstrate how ANG stimulates proliferation of myeloid progenitor cells, and maintains stem cells by inducing a state of cellular dormancy (quiescence), which is the first known evidence of ANG’s suppressive activity.

Through this quiescence state, it preserves stem cells over time, so they can be available in the future to help maintain immunity. In a different novel finding, researchers were able to demonstrate how ANG is able to achieve the dual functions by inducing RNA processing that is different in various cell types.

For example, in hematopoietic stem/progenitor cells, ANG induces processing of tiRNA that is quiescence-related while in myeloid progenitor cells, ANG induces the processing of rRNA that is proliferation related.

“Proper blood cell production is dependent on functioning hematopoietic stem and progenitor cells that are destroyed during conditioning procedures for transplantation or following bone marrow injury,” said first study author Kevin A. Goncalves. “Our study demonstrates that ANG regulates critical functions of both clinically-relevant cell types.”

Researchers also conducted additional studies that tested the capacity of ANG to prevent and mitigate radiation-induced bone marrow failure. In pre-clinical models, investigators discovered that survival after radiation exposure increased after treatment with recombinant ANG protein.