A team of researchers led by Professor Atsushi Iwama from The Institute of Medical Science, The University of Tokyo, announced on July 10 that activating specific proteins in the bone marrow microenvironment may enhance recovery following chemotherapy, radiation, or stem cell transplantation. Their findings were published in the journal Blood on June 22.
The study focused on hematopoietic stem cells (HSCs), which are responsible for generating blood cells and are often depleted during cancer treatments. Researchers investigated the roles of two transcriptional co-activators, YAP and TAZ, within the bone marrow niche—an environment composed of supporting cells such as endothelial cells (ECs) and mesenchymal stromal cells (MSCs).
Using mouse models with targeted gene knockouts, the team found that removing YAP/TAZ activity in MSCs led to reduced HSC numbers in bone marrow and increased mobilization into circulating blood. This suggested that basal YAP/TAZ activity is essential for retaining HSCs within the bone marrow. In contrast, knocking out these genes in hematopoietic cells had little effect under normal or post-injury conditions.
After exposure to radiation, mice lacking YAP/TAZ in MSCs showed impaired hematopoietic recovery. Loss of these proteins in ECs resulted in significant blood vessel dilation. Mechanistic studies indicated that YAP/TAZ regulate key transcription factors such as Ebf1 and Ebf3 to preserve MSC identity and promote production of factors necessary for hematopoiesis and angiogenesis.
The researchers also identified a small molecule inhibitor called GA-003 that increases YAP/TAZ activity by inhibiting LATS1/2 kinase. Administration of GA-003 after radiation enhanced bone marrow niche recovery and accelerated hematopoietic regeneration. The compound also improved engraftment following stem cell transplantation and worked synergistically with granulocyte colony-stimulating factor to further boost white blood cell recovery.
"Our new therapeutic approach addresses the limitation of supportive therapies and enhances the recovery of the BM niche, thereby enabling coordinated restoration of multiple blood cell lineages, including neutrophils, red blood cells, and platelets. This has the potential to improve the overall management of hematopoietic complications associated with chemotherapy, radiotherapy, and HSCT," concludes Prof. Iwama.
