Healthy bone marrow (BM) produces nearly every type of cell in the blood. Many blood diseases occur when hematopoietic stem cells (HSCs) within the BM become dysfunctional. Many blood diseases and cancers are treated with radiation and chemotherapy, which as a side effect depletes not only tumor cells but also hematopoietic cells, including HSCs, a BM condition known as myelosuppression.
In severe cases, HSC transplantation (HSCT) is required to restore hematopoiesis. The BM niche is a complex environment containing supporting cells such as endothelial cells (ECs) and mesenchymal stromal cells (MSCs) that maintain HSC activity. These cells are also damaged during myeloablative therapy, and inadequate recovery may reduce the effectiveness of chemotherapy and HSCT. However, the mechanisms underlying niche recovery in BM remain elusive, and therapeutic strategies targeting niche recovery remain underdeveloped.
To address this, a research team led by Professor Atsushi Iwama of the Institute of Medical Science, the University of Tokyo, together with Dr. Shun Uemura of the University of Tokyo Institute of Medical Science, Dr. Masayuki Yamashita of St. Jude Children’s Research Institute in the US, and Dr. Yasuto Nishino of Nissan Chemical Co., Ltd. in Japan, conducted a study to define the role of two transcriptional activators, YAP and TAZ, in the regenerating BM niche. It is used to evaluate the therapeutic potential of YAP/TAZ activation as well as hematopoiesis. Their findings were published in the magazine blood June 22, 2026.
The team generated a series of mouse models. Yap state/Taz Genes were specifically knocked out in either ECs, MSCs, or hematopoietic cells. Under steady-state conditions, MSC YAP/TAZ knockout mice exhibited reduced HSC numbers in the BM and increased HSC recruitment into the circulating blood, demonstrating that basal YAP/TAZ activity of MSCs is essential for HSC retention in the BM. In contrast, YAP/TAZ in hematopoietic cells was found to be largely dispensable under both steady-state and post-injury conditions.
Upon exposure to radiation, hematopoietic recovery was severely impaired in YAP/TAZ knockout mice in mesenchymal stem cells, whereas loss of YAP/TAZ in endothelial cells caused marked vasodilation, indicating that YAP/TAZ in both mesenchymal stem cells and endothelial cells play an important role in restoring the BM niche after injury. Mechanistically, YAP/TAZ regulates important transcription factors such as: Ebf1 and Ebf3 In MSCs, it maintains MSC identity and promotes the expression of hematopoietic factors such as: Cxcl12 and angiogenic factors.
Furthermore, YAP/TAZ in MSCs and ECs coordinately remodels sinusoidal vessels after BM injury. Altogether, these YAP/TAZ-mediated niche responses are essential for hematopoietic regeneration after myeloablative therapy.
Researchers also identified a small molecule called GA-003 that inhibits LATS1/2 kinase and increases YAP/TAZ activity. Administration of GA-003 to mice after radiation significantly accelerated BM niche recovery and promoted hematopoietic regeneration. GA-003 also promoted engraftment after HSCT and acted synergistically with granulocyte colony-stimulating factor, a drug commonly used to treat neutropenia, to further enhance white blood cell recovery.
Our study has the potential to have a major impact by introducing a new therapeutic concept that targets the BM niche rather than the hematopoietic cells themselves. It may stimulate further research on regeneration through microenvironments containing similar signaling pathways within tissues. ”
Atsushi Iwama Professor, Institute of Medical Science, University of Tokyo
In summary, the identification of pharmacological YAP/TAZ activation as a viable strategy provides the basis for future drug development targeting tissue niches and has the potential to expand research into niche-targeted therapeutics across regenerative medicine and disease contexts. By introducing a new conceptual framework that emphasizes the role of the tissue microenvironment in regeneration, it has the potential to impact a wide range of research fields.
“Our novel therapeutic approach addresses the limitations of supportive care and enhances recovery of the BM niche, thereby enabling coordinated recovery of multiple blood cell lineages, including neutrophils, red blood cells, and platelets. This may improve the overall management of chemotherapy, radiotherapy, and chemotherapy-related hematopoietic complications.” HSCT,” Professor Iwama concluded as follows.
sauce:
Reference magazines:
Susumu Uemura others. (2026) Niche-targeted therapy via YAP/TAZ activation promotes hematopoietic regeneration. blood journal. DOI: 10.1182/blood.2025030831. https://ashpublications.org/blood/article-abstract/doi/10.1182/blood.2025030831/569276/Niche-targeted-therapy-via-YAP-TAZ-activation?redirectedFrom=fulltext.
