YAP/TAZ-dependent niche remodeling drives hematopoietic regeneration

The distinctive milieu of bone marrow (BM), termed BM niche, supports hematopoietic stem and progenitor cells (HSPCs) and serves as a foundation for hematopoietic regeneration. Myeloablative stress disrupts not only hematopoietic cells but also niche components, including endothelial cells (ECs) and mesenchymal stromal cells (MSCs), the latter of which restrains efficient hematopoietic recovery. YAP/TAZ are the two transcriptional coactivators downstream of the Hippo pathway and are essential for the regeneration of various organs8,9. However, their role in the BM niche remained unexplored. Here, we show that YAP/TAZ activation in BM ECs and MSCs triggered by myeloablative stress is critical for BM niche remodeling and hematopoietic regeneration. We found that YAP/TAZ activity in MSCs promotes the maintenance of HSPCs in the BM. Furthermore, YAP/TAZ activation in MSCs and ECs is critical for the initiation and termination of vascular remodeling after myeloablation, respectively. Mechanistically, YAP/TAZ in MSCs directly activate the transcription of Cxcl12 to maintain HSPCs, transcriptional regulators to restrict MSC differentiation, and angiogenic factors to control vascular remodeling. Administration of a novel YAP/TAZ activator significantly accelerates niche remodeling after myeloablation, thereby promoting hematopoietic regeneration. These results indicate that YAP/TAZ activity orchestrates BM niche organization and remodeling, providing niche-targeted therapy to enhance hematopoietic resilience against myeloablative insults.