Cutting the brakes on hematopoietic regeneration by blocking TGFβ to limit chemotherapy-induced myelosuppression.
Hematopoietic stressors such as infection, bleeding, or toxic injury trigger a hematopoietic adaptation that sacrifices hematopoietic stem and progenitor cell (HSPC) quiescence to meet an urgent need for new blood cell production. Once the hematopoietic demands are adequately met, homeostasis must be restored. Transforming growth factor β (TGFβ) signaling is a central mediator mandating the return of HSPCs to quiescence after stress. Blockade of TGFβ signaling after hematopoietic stress delays the return of cycling HSPCs to quiescence and in so doing promotes hematopoietic stem cell (HSC) self-renewal and accelerates hematopoietic reconstitution. These findings open the door to new therapeutics that modulate the hematopoietic adaptation to stress. In this review, we will discuss the complex context-dependent activities of TGFβ in hematopoiesis and the potential benefits and limitations of using TGFβ pathway inhibitors to promote multilineage hematopoietic reconstitution after myelosuppressive chemotherapy.
Inserm U1068, Centre de Recherche en Cancérologie de Marseille (CRCM), Signaling, Hematopoiesis and Mechanisms of Oncogenesis; Institut Paoli-Calmettes; Aix-Marseille Université UM 105, CNRS UMR 7258 ; Marseille, France.
Fabienne
F
Brenet
Department of Medicine; Divisions of Hematology-Oncology and Regenerative Medicine; Laboratory of Molecular Hematopoiesis; Weill Cornell Medical College; New York, NY; Weill Cornell Medical College; Regenerative Medicine, Laboratory of Molecular Hematopoiesis; New York, NY USA.
Joseph M
JM
Scandura
Smad; TGFβ; bone marrow recovery; context-dependent regulation; hematologic stress; hematopoiesis; hematopoietic stem cell; homeostasis; inhibitors; myelosuppression; p57; quiescence