Specialized therapies offer a new approach to regenerative medicine

A healthy bone marrow (BM) produces almost all the types of cells in our blood. Many blood disorders occur when hematopoietic stem cells (HSCs) in the BM malfunction. Many hematologic disorders and cancers are treated with radiation or chemotherapy, which as a side effect destroys not only cancer cells but also hematopoietic cells, including HSCs in the BM—a condition known as myelosuppression.

In severe cases, HSC transplantation (HSCT) is required to restore hematopoiesis. The BM niche is a complex environment that includes supporting cells such as endothelial cells (ECs) and mesenchymal stromal cells (MSCs) that maintain HSC activity. These cells are also destroyed during myeloablative treatments, and their poor recovery can lead to reduced efficacy of chemotherapy and HSCT. However, the mechanisms underlying the recovery of BM niches remain unclear, and therapeutic strategies targeting the recovery of specialized niches are poorly developed.

To address this, a team of researchers led by Professor Atsushi Iwama from the Institute of Medical Science, University of Tokyo, Japan, along with Dr. Shun Uemura from the Institute of Medical Science, University of Tokyo, Japan, Dr. Masayuki Yamashita from St. Jude Children’s Research Hospital, USA, and Dr. the role of two transcriptional co-activators YAP and TAZ in the BM niche during regenerative hematopoiesis, as well as evaluating the therapeutic potential of YAP/TAZ activation. Their findings were published in the journal Blood on June 22, 2026.

The team created a series of mouse models where BARKING/TAZ genes were specifically blocked in either ECs, MSCs or hematopoietic cells. Under steady-state conditions, YAP/TAZ knockout mice in MSCs showed reduced HSC numbers in the BM and increased HSC mobilization in the circulating blood, demonstrating that basal YAP/TAZ activity in MSCs is essential for the maintenance of HSCs in the BM. In contrast, YAP/TAZ in hematopoietic cells was found to be largely non-dispensable in both steady-state and post-injury conditions.

When exposed to radiation, hematopoietic recovery was significantly impaired in YAP/TAZ knockout mice in MSCs, while loss of YAP/TAZ in ECs led to marked vasodilation, indicating that YAP/TAZ in both MSCs and ECs plays a critical role in the recovery of BM niche after injury. Mechanistically, YAP/TAZ regulates key transcription factors such as Ebf1 and Ebf3 in MSCs, maintaining the identity of MSCs and promoting the expression of hematopoietic factors such as e.g Cxcl12 and angiogenic factors.

Moreover, YAP/TAZ in MSCs and ECs coordinately remodel sinusoidal vasculature after BM injury. Taken together, these specialized YAP/TAZ-mediated responses are essential for hematopoietic regeneration after myeloablative therapies.

The researchers also identified a small molecule called GA-003 that inhibits LATS1/2 kinase and increases YAP/TAZ activity. When mice were given GA-003 after irradiation, recovery of the BM site was significantly enhanced and hematopoietic regeneration was accelerated. 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 may have a significant impact by introducing a new therapeutic concept that targets the location of the BM and not the hematopoietic cells themselves. It may stimulate further studies of microenvironment-based regeneration involving similar signaling pathways in 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 development of drugs targeting tissue sites, potentially expanding research into specialized therapies in regenerative medicine and disease settings. It can impact a wide range of research fields by introducing a new conceptual framework that emphasizes the role of the tissue microenvironment in regeneration.

“Our novel therapeutic approach addresses the limitation of supportive therapies and enhances the recovery of BM niche, thus allowing coordinated recovery 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, radiation therapy HSCT,“ Prof. Iwama concludes.