Niche-targeted therapy via YAP/TAZ activation enhances hematopoietic regeneration

ABSTRACT: The distinctive milieu of the bone marrow (BM), known as the BM niche, supports hematopoietic stem cells (HSCs) and serves as a foundation for hematopoietic regeneration. Myeloablative stress disrupts not only hematopoietic stem and progenitor cells but also essential BM niche components, including endothelial cells (ECs) and mesenchymal stromal cells (MSCs); disruption of the latter impairs efficient hematopoietic recovery. However, therapeutic strategies targeting niche restoration remain largely underdeveloped. Here, we demonstrate that the Hippo pathway effectors YAP and TAZ are critical for enabling ECs and MSCs to respond to BM injury, and that YAP/TAZ activation accelerates BM niche recovery, thereby promoting hematopoietic regeneration. We found that YAP and TAZ are rapidly activated in both MSCs and ECs after myeloablative stress, maintaining MSC multipotency and orchestrating vascular remodeling. Mechanistically, YAP and TAZ function as transcriptional hubs in MSCs, regulating key transcription factors such as Ebf1 and Ebf3. This regulation preserves MSC identity by preventing osteogenic and fibrogenic differentiation while promoting the expression of hematopoietic factors such as Cxcl12 and angiogenic factors. In addition, YAP/TAZ signaling in MSCs and ECs appeared to coordinately remodel sinusoidal vessels after BM injury. These YAP/TAZ-mediated niche responses are essential for HSC retention and hematopoietic regeneration after diverse myelosuppressive therapies. Notably, pharmacological activation of YAP/TAZ enhances BM niche reorganization and augments hematopoietic regeneration after myeloablative therapies. These findings establish YAP/TAZ as central regulators of BM niche resilience, providing a rationale for niche-targeted therapeutic strategies to enhance hematopoietic regeneration.