Enhancing Hematopoietic Recovery: The Crucial Role of YAP/TAZ in Bone Marrow Niche Restoration

Adult hematopoietic stem cells (HSCs) are maintained within a specific bone marrow environment known as the HSC niche, which is primarily composed of vascular endothelial cells and mesenchymal stromal cells. Stresses such as radiation and chemotherapy not only deplete blood-forming cells but also damage the HSC niche, hindering the recovery process and impacting the success of stem cell transplants and chemotherapy. YAP/TAZ, transcriptional coactivators regulated by the Hippo signaling pathway, have been linked to tissue repair, but their role in bone marrow recovery has been less clear.

Our study discovered that YAP/TAZ are highly expressed in mouse endothelial and mesenchymal cells but not in HSCs. Following a mild dose of radiation, YAP/TAZ in endothelial cells are temporarily activated, which is crucial for maintaining blood vessel integrity. Conversely, their activity in mesenchymal cells is temporarily reduced, affecting their ability to form colonies.

We identified GA-003, a compound that can activate YAP/TAZ in vitro. When administered to mice after radiation, GA-003 significantly accelerated the recovery of blood cell production. The treatment also improved recovery after chemotherapy and stem cell transplantation, without directly affecting the growth of blood stem cells, indicating a niche-mediated effect.

Further investigation showed that GA-003 reduced blood vessel dilation and leakage and promoted the repair of blood vessels, as evidenced by increased VE-Cadherin expression in endothelial cells. These findings suggest that enhancing YAP/TAZ activity can protect the HSC niche and speed up blood cell regeneration, positioning YAP/TAZ as potential therapeutic targets for improving recovery post-chemotherapy and stem cell transplant.