TGF-β1-triggered maladaptive bone marrow endothelium impedes hematopoietic recovery

Endothelial cells (ECs) form a critical bone marrow (BM) niche for hematopoietic stem cell regulation in homeostasis and stress states. However, BM ECs are frequently disrupted in hematologic diseases and their clinical interventions. Although transient EC injury is repairable, chronic activation of stress signals often induces maladaptive EC repair, which is a state of fibrotic reprogramming characterized by the loss of BM EC-specific functions and impaired hematopoietic-supporting ability. Although TGF-β1 (a pleiotropic cytokine) is implicated in angiogenesis and tissue repair, its role in driving BM EC maladaptation remains undefined. Here, in vitro experiments combined with a mouse model with adeno-associated virus-mediated BM EC-specific overexpression of constitutively active TGF-βRI demonstrated that TGF-β1 activation drives maladaptive BM ECs, characterized by defective vascular regeneration and impaired hematopoietic-supporting abilities. Multiomics profiling (transcriptomic and phosphoproteomic analyses) demonstrated a mechanistic link between maladaptive BM EC repair and a TGF-β1-induced secretome shift, characterized by the suppression of hematopoietic-supportive factors and the upregulation of epithelial-mesenchymal transition mediators. This effect may be driven by dysregulated vascular endothelial growth factor receptor/Notch crosstalk and subsequent p38α activation. Clinically, BM ECs from poor graft function (PGF) patients post-transplantation exhibited hyperactivated TGF-β1 signaling. In vitro experiments revealed TGF-β1 inhibition restored the function of maladaptive BM ECs from PGF patients. Subsequently, a prospective single-arm study involving luspatercept (a TGF-β ligand trap) demonstrated the significant promotion of multilineage hematopoiesis recovery in post-transplantation patients (NCT05629260). Therefore, our findings suggest that TGF-β1 may be a critical driver of BM EC maladaptation and highlight therapeutic TGF-β1 pathway inhibition for hematopoietic regeneration via BM EC remodeling.